Biochemistry of Alzheimer's disease: Difference between revisions

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The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain.^[1] Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development.^[2] The presenilins are components of proteolytic complex involved in APP processing and degradation.^[3]^[4]

Amyloid beta monomers are soluble and contain short regions of beta sheet and polyproline II helix secondary structures in solution,^[5] though they are largely alpha helical in membranes;^[6] however, at sufficiently high concentration, they undergo a dramatic conformational change to form a beta sheet-rich tertiary structure that aggregates to form amyloid fibrils.^[7] These fibrils deposit outside neurons in dense formations known as senile plaques or neuritic plaques, in less dense aggregates as diffuse plaques, and sometimes in the walls of small blood vessels in the brain in a process called cerebral amyloid angiopathy.

AD is also considered a tauopathy due to abnormal aggregation of the tau protein, a microtubule-associated protein expressed in neurons that normally acts to stabilize microtubules in the cell cytoskeleton. Like most microtubule-associated proteins, tau is normally regulated by phosphorylation; however, in Alzheimer's disease, hyperphosphorylated tau accumulates as paired helical filaments^[8] that in turn aggregate into masses inside nerve cell bodies known as neurofibrillary tangles and as dystrophic neurites associated with amyloid plaques. Although little is known about the process of filament assembly, it has recently been shown that a depletion of a prolyl isomerase protein in the parvulin family accelerates the accumulation of abnormal tau.^[9]^[10]

Neuroinflammation is also involved in the complex cascade leading to AD pathology and symptoms. Considerable pathological and clinical evidence documents immunological changes associated with AD, including increased pro-inflammatory cytokine concentrations in the blood and cerebrospinal fluid.^[11]^[12] Whether these changes may be a cause or consequence of AD remains to be fully understood, but inflammation within the brain, including increased reactivity of the resident microglia towards amyloid deposits, has been implicated in the pathogenesis and progression of AD.^[13]

Neuropathology

At a macroscopic level, AD is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.^[14]

Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains.^[15] Plaques are dense, mostly insoluble deposits of protein and cellular material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.^[16]

Biochemical characteristics

Fundamental to the understanding of Alzheimer's disease is the biochemical events that leads to accumulation of the amyloid-beta and tau-protein. A delicate balance of the enzymes secretases regulate the amyloid-beta accumulation. Alpha Secretase can render a non-pathological (non-amyloidogenic) Amyloid Beta (DOI: 10.2174/156720512799361655). Recently, a link between cholinergic neuronal activity and the activity of alpha-secretase has been highlighted,^[17] which can discourage Amyloid-beta proteins deposition in brain of patients with Alzheimer's Disease. Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded Amyloid-beta proteins in the brains of AD patients.^[1] Abnormal amyloid-beta accumulation can first be detected using cerebrospinal fluid analysis and later using positron emission tomography (PET).^[18]

Although AD shares pathophysiological mechanisms with prion diseases, it is not transmissible like prion diseases.^[19] Amyloid-beta, also written Aβ, is a short peptide that is a proteolytic byproduct of the transmembrane protein amyloid precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of a proteolytic complex involved in APP processing and degradation.^[4] Although amyloid beta monomers are harmless, they undergo a dramatic conformational change at sufficiently high concentration to form a beta sheet-rich tertiary structure that aggregates to form amyloid fibrils^[7] that deposit outside neurons in dense formations known as senile plaques or neuritic plaques, in less dense aggregates as diffuse plaques, and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy or congophilic angiopathy.

AD is also considered a tauopathy due to abnormal aggregation of the tau protein, a microtubule-associated protein expressed in neurons that normally acts to stabilize microtubules in the cell cytoskeleton. Like most microtubule-associated proteins, tau is normally regulated by phosphorylation; however, in AD patients, hyperphosphorylated tau accumulates as paired helical filaments^[8] that in turn aggregate into masses inside nerve cell bodies known as neurofibrillary tangles and as dystrophic neurites associated with amyloid plaques.

Levels of the neurotransmitter acetylcholine (ACh) are reduced. Levels of other neurotransmitters serotonin, norepinephrine, and somatostatin are also often reduced. Replenishing the ACh by anti-cholinesterases is an approved mode of treatment by FDA. An alternative method of stimulating ACh receptors of M1-M3 types by synthetic agonists that have a slower rate of dissociation from the receptor has been proposed as next generation cholinomimetic in Alzheimer's disease^[15].

Potential disease mechanisms

While the gross histological features of AD in the brain have been well characterized, several different hypotheses have been advanced regarding the primary cause. Among the oldest hypotheses is the cholinergic hypothesis, which suggests that deficiency in cholinergic signaling initiates the progression of the disease^[20]. Other hypotheses suggest that either misfolding tau protein inside the cell or aggregation of amyloid beta outside the cell initiates the cascade leading to AD pathology^[21]^[22]>. Still other hypotheses propose metabolic factors^[23], vascular disturbance^[24], or chronically elevated inflammation in the brain^[25] as the primary cause for AD. While researchers have not identified a clear causative pathway originating from any of the molecular hypothesis that explains the gross anatomical changes observed in advanced AD, variants of the amyloid beta hypothesis of molecular initiation have become dominant among many researchers to date^[26]

Cholinergic hypothesis

The cholinergic hypothesis of AD development was first proposed in 1976 by Peter Davies and A.J.F Maloney.^[27] It states that Alzheimer's begins as a deficiency in the production of acetylcholine, a vital neurotransmitter. Much early therapeutic research was based on this hypothesis, including restoration of the "cholinergic nuclei". The possibility of cell-replacement therapy was investigated on the basis of this hypothesis. All of the first-generation anti-Alzheimer's medications are based on this hypothesis and work to preserve acetylcholine by inhibiting acetylcholinesterases (enzymes that break down acetylcholine). These medications, though sometimes beneficial, have not led to a cure. In all cases, they have served to only treat symptoms of the disease and have neither halted nor reversed it. These results and other research have led to the conclusion that acetylcholine deficiencies may not be directly causal, but are a result of widespread brain tissue damage, damage so widespread that cell-replacement therapies are likely to be impractical.

More recent hypotheses center on the effects of the misfolded and aggregated proteins, amyloid beta and tau. The two positions are lightheartedly described as "ba-ptist" and "tau-ist" viewpoints in one scientific publication. Therein, it is suggested that "Tau-ists" believe that the tau protein abnormalities initiate the disease cascade, while "ba-ptists" believe that beta amyloid deposits are the causative factor in the disease.^[28]

Tau hypothesis

The hypothesis that tau is the primary causative factor has long been grounded in the observation that deposition of amyloid plaques does not correlate well with neuron loss.^[29] A mechanism for neurotoxicity has been proposed based on the loss of microtubule-stabilizing tau protein that leads to the degradation of the cytoskeleton.^[30] However, consensus has not been reached on whether tau hyperphosphorylation precedes or is caused by the formation of the abnormal helical filament aggregates.^[28] Support for the tau hypothesis also derives from the existence of other diseases known as tauopathies in which the same protein is identifiably misfolded.^[31] However, a majority of researchers support the alternative hypothesis that amyloid is the primary causative agent.^[28]

Amyloid hypothesis

The amyloid hypothesis is initially compelling because the gene for the amyloid beta precursor APP is located on chromosome 21, and patients with trisomy 21 - better known as Down syndrome - who have an extra gene copy exhibit AD-like disorders by 40 years of age.^[32]^[33] The amyloid hypothesis points to the cytotoxicity of mature aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis and thus inducing apoptosis.^[34] This hypothesis is supported by the observation that higher levels of a variant of the beta amyloid protein known to form fibrils faster in vitro correlate with earlier onset and greater cognitive impairment in mouse models^[35] and with AD diagnosis in humans.^[36] However, mechanisms for the induced calcium influx, or proposals for alternative cytotoxic mechanisms, by mature fibrils are not obvious.^{[clarification needed]}

A more recent variation of the amyloid hypothesis identifies the cytotoxic species as an intermediate misfolded form of amyloid beta, neither a soluble monomer nor a mature aggregated polymer but an oligomeric species, possibly toroidal or star-shaped with a central channel^[37] that may induce apoptosis by physically piercing the cell membrane.^[38] This ion channel hypothesis postulates that oligomers of soluble, non-fibrillar Aβ form membrane ion channels allowing unregulated calcium influx into neurons.^[39] A related alternative suggests that a globular oligomer localized to dendritic processes and axons in neurons is the cytotoxic species.^[40]^[41] The prefibrillar aggregates were shown to be able to disrupt the membrane.^[42]

The cytotoxic-fibril hypothesis presents a clear target for drug development: inhibit the fibrillization process. Much early development work on lead compounds has focused on this inhibition;^[43]^[44]^[45] most are also reported to reduce neurotoxicity, but the toxic-oligomer theory would imply that prevention of oligomeric assembly is the more important process^[46]^[47] ^[48] or that a better target lies upstream, for example in the inhibition of APP processing to amyloid beta.^[49] For example, apomorphine was seen to significantly improve memory function through the increased successful completion of the Morris Water Maze.^[46]

Soluble intracellular (o)Aβ42

Two papers have shown that oligomeric (o)Aβ42 (a species of Aβ), in soluble intracellular form, acutely inhibits synaptic transmission, a pathophysiology that characterizes AD (in its early stages), by activating casein kinase 2.^[50]^[51]

Inflammatory Hypothesis

Converging evidence suggests/supports that a sustained inflammatory response in the brain is a core feature of AD pathology and may be a key factor in AD pathogenesis^[52]^[53]. The brains of AD patients exhibit several markers of increased inflammatory signaling^[54]^[55]^[56]. The inflammatory hypothesis proposes that chronically elevated inflammation in the brain is a crucial component to the amyloid cascade^[57] in the early phases of AD and magnifies disease severity in later stages of AD. Aβ is present in healthy brains and serves a vital physiological function in recovery from neuronal injury, protection from infection, and repair of the blood-brain barrier^[58], however it is unknown how Aβ production starts to exceed the clearance capacity of the brain and initiates AD progression. A possible explanation is that Aβ causes microglia, the resident immune cell of the brain, to become activated and secrete pro-inflammatory signaling molecules, called cytokines, which recruit other local microglia^[59]. While acute microglial activation, as in response to injury, is beneficial and allows microglia to clear Aβ and other cellular debris via phagocytosis, chronically activated microglia exhibit decreased efficiency in Aβ clearance^[60]. Despite this reduced AB clearance capacity, activated microglia continue to secrete pro-inflammatory cytokines like interleukins 1β and 6 (IL-6, IL-1β) and tumor necrosis factor-alpha (TNF-a), as well as reactive oxygen species which disrupt healthy synaptic functioning^[61] and eventually cause neuronal death^[62]. The loss of synaptic functioning and later neuronal death is responsible for the cognitive impairments and loss of volume in key brain regions which are associated with AD^[63]. IL-1B, IL-6, and TNF-a cause further production of Aβ oligomers, as well as tau hyperphosphorylation, leading to continued microglia activation and creating a feed forward mechanism in which Aβ production is increased and Aβ clearance is decreased eventually causing the formation of Aβ plaques^[64]^[65].

Isoprenoid changes

A 1994 study ^[66] showed that the isoprenoid changes in Alzheimer's disease differ from those occurring during normal aging and that this disease cannot, therefore, be regarded as a result of premature aging. During aging the human brain shows a progressive increase in levels of dolichol, a reduction in levels of ubiquinone, but relatively unchanged concentrations of cholesterol and dolichyl phosphate. In Alzheimer's disease, the situation is reversed with decreased levels of dolichol and increased levels of ubiquinone. The concentrations of dolichyl phosphate are also increased, while cholesterol remains unchanged. The increase in the sugar carrier dolichyl phosphate may reflect an increased rate of glycosylation in the diseased brain and the increase in the endogenous anti-oxidant ubiquinone an attempt to protect the brain from oxidative stress, for instance induced by lipid peroxidation.^[67] Ropren, identified previously in Russia, is neuroprotective in a rat model of Alzheimer's disease.^[68]^[69]

Glucose consumption

The human brain is one of the most metabolically active organs in the body and metabolizes a large amount of glucose to produce cellular energy in the form of adenosine triphosphate (ATP).^[70] Despite its high energy demands, the brain is relatively inflexible in its ability to utilize substrates for energy production and relies almost entirely on circulating glucose for its energy needs.^[71] This dependence on glucose puts the brain at risk if the supply of glucose is interrupted, or if its ability to metabolize glucose becomes defective. If the brain is not able to produce ATP, synapses cannot be maintained and cells cannot function, ultimately leading to impaired cognition.^[71]

Imaging studies have shown decreased utilization of glucose in the brains of Alzheimer’s disease patients early in the disease, before clinical signs of cognitive impairment occur. This decrease in glucose metabolism worsens as clinical symptoms develop and the disease progresses.^[72]^[73] Studies have found a 17%-24% decline in cerebral glucose metabolism in patients with Alzheimer’s disease, compared with age-matched controls.^[74] Numerous imaging studies have since confirmed this observation.

Abnormally low rates of cerebral glucose metabolism are found in a characteristic pattern in the Alzheimer’s disease brain, particularly in the posterior cingulate, parietal, temporal, and prefrontal cortices. These brain regions are believed to control multiple aspects of memory and cognition. This metabolic pattern is reproducible and has even been proposed as a diagnostic tool for Alzheimer’s disease. Moreover, diminished cerebral glucose metabolism (DCGM) correlates with plaque density and cognitive deficits in patients with more advanced disease.^[74]^[75]

Diminished cerebral glucose metabolism (DCGM) may not be solely an artifact of brain cell loss since it occurs in asymptomatic patients at risk for Alzheimer’s disease, such as patients homozygous for the epsilon 4 variant of the apolipoprotein E gene (APOE4, a genetic risk factor for Alzheimer’s disease), as well as in inherited forms of Alzheimer’s disease.^[76] Given that DCGM occurs before other clinical and pathological changes occur, it is unlikely to be due to the gross cell loss observed in Alzheimer’s disease.^[71]

In imaging studies involving young adult APOE4 carriers, where there were no signs of cognitive impairment, diminished cerebral glucose metabolism (DCGM) was detected in the same areas of the brain as older subjects with Alzheimer’s disease.^[76] However, DCGM is not exclusive to APOE4 carriers. By the time Alzheimer’s has been diagnosed, DCGM occurs in genotypes APOE3/E4, APOE3/E3, and APOE4/E4.^[77] Thus, DCGM is a metabolic biomarker for the disease state.^[78]

Insulin signaling

A connection has been established between Alzheimer's disease and diabetes during the past decade, as insulin resistance, which is a characteristic hallmark of diabetes, has also been observed in brains of subjects suffering from Alzheimer's disease.^[79] Neurotoxic oligomeric amyloid-β species decrease the expression of insulin receptors on the neuronal cell surface^[80] and abolish neuronal insulin signaling.^[79] It has been suggested that neuronal gangliosides, which take part in the formation of membrane lipid microdomains, facilitate amyloid-β-induced removal of the insulin receptors from the neuronal surface.^[81] In Alzheimer's disease, oligomeric amyloid-β species trigger TNF-α signaling.^[79] c-Jun N-terminal kinase activation by TNF-α in turn activates stress-related kinases and results in IRS-1 serine phosphorylation, which subsequently blocks downstream insulin signaling.^[79]^[82]^[83] The resulting insulin resistance contributes to cognitive impairment. Consequently, increasing neuronal insulin sensitivity and signaling may constitute a novel therapeutic approach to treat Alzheimer's disease.^[84]^[85]

Oxidative stress

Oxidative stress is emerging as a key factor in the pathogenesis of AD.^[86] Reactive oxygen species (ROS) over-production is thought to play a critical role in the accumulation and deposition of amyloid beta in AD.^[87] Brains of AD patients have elevated levels of oxidative DNA damage in both nuclear and mitochondrial DNA, but the mitochondrial DNA has approximately 10-fold higher levels than nuclear DNA.^[88] Aged mitochondria may be the critical factor in the origin of neurodegeneration in AD.^[87] Even individuals with mild cognitive impairment, the phase between normal aging and early dementia, have increased oxidative damage in their nuclear and mitochondrial brain DNA^[89] (see Aging brain).

Large gene instability hypothesis

A bioinformatics analysis in 2017^[90] revealed that extremely large human genes are significantly over-expressed in brain and take part in the postsynaptic architecture. These genes are also highly enriched in cell adhesion Gene Ontology (GO) terms and often map to chromosomal fragile sites.^[91] The majority of known Alzheimer's disease risk gene products including the amyloid precursor protein (APP) and gamma-secretase, as well as the APOE receptors and GWAS risk loci take part in similar cell adhesion mechanisms. It was concluded that dysfunction of cell and synaptic adhesion is central to Alzheimer's disease pathogenesis, and mutational instability of large synaptic adhesion genes may be the etiological trigger of neurotransmission disruption and synaptic loss in brain aging. As a typical example, this hypothesis explains the APOE risk locus of AD in context of signaling of its giant lipoprotein receptor, LRP1b which is a large tumor-suppressor gene with brain-specific expression and also maps to an unstable chromosomal fragile site. The large gene instability hypothesis puts the DNA damage mechanism at the center of Alzheimer's disease pathophysiology.

DNA damage

Naturally occurring DNA double-strand breaks (DSBs) arise in human cells largely from single-strand breaks induced by various processes including the activity of reactive oxygen species, topoisomerases, and hydrolysis due to thermal fluctuations.^[92] In neurons DSBs are induced by a type II topoisomerase as part of the physiologic process of memory formation.^[93] DSBs are present in both neurons and astrocytes in the postmortem human hippocampus of AD patients at a higher level than in non-AD individuals.^[94] AD is associated with an accumulation of DSBs in neurons and astrocytes in the hippocampus and frontal cortex from early stages onward.^[95] DSBs are increased in the vicinity of amyloid plaques in the hippocampus, indicating a potential role for Aβ in DSB accumulation or vice versa.^[94] The predominant mechanism for repairing DNA double-strand breaks is non-homologous end joining (NHEJ), a mechanism that utilizes the DNA-dependent protein kinase (DNA-PK) complex. The end joining activity and protein levels of DNA-PK catalytic subunit are significantly lower in AD brains than in normal brains.^[96]

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-The '''biochemistry of Alzheimer's disease''', the most common cause of [[dementia]], is not yet very well understood. [[Alzheimer's disease]] (AD) has been identified as a [[proteopathy]] a [[protein folding|protein misfolding]] disease due to the accumulation of abnormally folded [[amyloid beta]] (Aβ) protein in the [[human brain|brain]].<ref name="Hashimoto">{{cite journal |vauthors=Hashimoto M, Rockenstein E, Crews L, Masliah E |title=Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases |journal=Neuromolecular Med. |volume=4 |issue=1–2 |pages=21–36 |year=2003 |pmid=14528050 |doi=10.1385/NMM:4:1-2:21}}</ref> Amyloid beta is a short [[peptide]] that is an abnormal [[proteolysis|proteolytic]] byproduct of the [[transmembrane protein]] [[amyloid-beta precursor protein]] (APP), whose function is unclear but thought to be involved in neuronal development.<ref name="Kerr">{{cite journal |vauthors=Kerr ML, Small DH |title=Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, regulation of proteolysis, and implications for drug development |journal=J. Neurosci. Res. |volume=80 |issue=2 |pages=151–9 |year=2005 |pmid=15672415 |doi=10.1002/jnr.20408}}</ref>  The [[presenilin]]s are components of proteolytic complex involved in APP processing and degradation.<ref>{{Cite journal|last=Borchelt|first=D.R|date=January 1998|title=Metabolism of Presenilin 1: Influence of Presenilin 1 on Amyloid Precursor Protein Processing|url=https://linkinghub.elsevier.com/retrieve/pii/S0197458098000268|journal=Neurobiology of Aging|language=en|volume=19|issue=1|pages=S15–S18|doi=10.1016/S0197-4580(98)00026-8}}</ref><ref name="Cai">{{cite journal |vauthors=Cai D, Netzer WJ, Zhong M |title=Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=103 |issue=6 |pages=1941–6 |year=2006 |pmid=16449386 |doi=10.1073/pnas.0510708103 |pmc=1413665|bibcode = 2006PNAS..103.1941C |display-authors=etal}}</ref>
+The '''biochemistry of Alzheimer's disease''', the most common cause of [[dementia]], is not yet very well understood. [[Alzheimer's disease]] (AD) has been identified as a [[proteopathy]] a [[protein folding|protein misfolding]] disease due to the accumulation of abnormally folded [[amyloid beta]] (Aβ) protein in the [[human brain|brain]].<ref name="Hashimoto">{{cite journal | vauthors = Hashimoto M, Rockenstein E, Crews L, Masliah E | title = Role of protein aggregation in mitochondrial dysfunction and neurodegeneration in Alzheimer's and Parkinson's diseases | journal = Neuromolecular Medicine | volume = 4 | issue = 1-2 | pages = 21–36 | year = 2003 | pmid = 14528050 | doi = 10.1385/NMM:4:1-2:21 }}</ref> Amyloid beta is a short [[peptide]] that is an abnormal [[proteolysis|proteolytic]] byproduct of the [[transmembrane protein]] [[amyloid-beta precursor protein]] (APP), whose function is unclear but thought to be involved in neuronal development.<ref name="Kerr">{{cite journal | vauthors = Kerr ML, Small DH | title = Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, regulation of proteolysis, and implications for drug development | journal = Journal of Neuroscience Research | volume = 80 | issue = 2 | pages = 151–9 | date = April 2005 | pmid = 15672415 | doi = 10.1002/jnr.20408 }}</ref>  The [[presenilin]]s are components of proteolytic complex involved in APP processing and degradation.<ref>{{cite journal | vauthors = Borchelt DR | title = Metabolism of presenilin 1: influence of presenilin 1 on amyloid precursor protein processing | journal = Neurobiology of Aging | volume = 19 | issue = 1 Suppl | pages = S15-8 | date = January 1998 | pmid = 9562461 | doi = 10.1016/S0197-4580(98)00026-8 }}</ref><ref name="Cai">{{cite journal | vauthors = Cai D, Netzer WJ, Zhong M, Lin Y, Du G, Frohman M, Foster DA, Sisodia SS, Xu H, Gorelick FS, Greengard P | display-authors = 6 | title = Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 6 | pages = 1941–6 | date = February 2006 | pmid = 16449386 | pmc = 1413665 | doi = 10.1073/pnas.0510708103 | bibcode = 2006PNAS..103.1941C }}</ref>
-Amyloid beta [[monomer]]s are soluble and contain short regions of [[beta sheet]] and [[polyproline helix|polyproline II helix]] [[secondary structure]]s in solution,<ref name="Danielsson">{{cite journal |vauthors=Danielsson J, Andersson A, Jarvet J, Gräslund A |title=15N relaxation study of the amyloid beta-peptide: structural propensities and persistence length |journal=Magnetic Resonance in Chemistry |volume=44 Spec No |pages=S114–21 |year=2006 |pmid=16826550 |doi=10.1002/mrc.1814}}</ref> though they are largely [[alpha helix|alpha helical]] in membranes;<ref name="Tomaselli">{{cite journal |vauthors=Tomaselli S, Esposito V, Vangone P |title=The alpha-to-beta conformational transition of Alzheimer's Abeta-(1-42) peptide in aqueous media is reversible: a step by step conformational analysis suggests the location of beta conformation seeding |journal=ChemBioChem |volume=7 |issue=2 |pages=257–67 |year=2006 |pmid=16444756 |doi=10.1002/cbic.200500223|display-authors=etal|hdl=1874/20092 |hdl-access=free }}</ref> however, at sufficiently high concentration, they undergo a dramatic [[conformational change]] to form a [[beta sheet]]-rich [[tertiary structure]] that aggregates to form [[amyloid|amyloid fibril]]s.<ref name="Ohnishi">{{cite journal |vauthors=Ohnishi S, Takano K |title=Amyloid fibrils from the viewpoint of protein folding |journal=Cell. Mol. Life Sci. |volume=61 |issue=5 |pages=511–24 |year=2004 |pmid=15004691 |doi=10.1007/s00018-003-3264-8}}</ref> These fibrils deposit outside neurons in dense formations known as [[senile plaques]] or [[neuritic plaques]], in less dense aggregates as ''diffuse plaques'', and sometimes in the walls of small blood vessels in the brain in a process called [[cerebral amyloid angiopathy]].
+Amyloid beta [[monomer]]s are soluble and contain short regions of [[beta sheet]] and [[polyproline helix|polyproline II helix]] [[secondary structure]]s in solution,<ref name="Danielsson">{{cite journal | vauthors = Danielsson J, Andersson A, Jarvet J, Gräslund A | title = 15N relaxation study of the amyloid beta-peptide: structural propensities and persistence length | journal = Magnetic Resonance in Chemistry | volume = 44 Spec No | pages = S114-21 | date = July 2006 | pmid = 16826550 | doi = 10.1002/mrc.1814 }}</ref> though they are largely [[alpha helix|alpha helical]] in membranes;<ref name="Tomaselli">{{cite journal | vauthors = Tomaselli S, Esposito V, Vangone P, van Nuland NA, Bonvin AM, Guerrini R, Tancredi T, Temussi PA, Picone D | display-authors = 6 | title = The alpha-to-beta conformational transition of Alzheimer's Abeta-(1-42) peptide in aqueous media is reversible: a step by step conformational analysis suggests the location of beta conformation seeding | journal = Chembiochem | volume = 7 | issue = 2 | pages = 257–67 | date = February 2006 | pmid = 16444756 | doi = 10.1002/cbic.200500223 | hdl-access = free | hdl = 1874/20092 }}</ref> however, at sufficiently high concentration, they undergo a dramatic [[conformational change]] to form a [[beta sheet]]-rich [[tertiary structure]] that aggregates to form [[amyloid|amyloid fibril]]s.<ref name="Ohnishi">{{cite journal | vauthors = Ohnishi S, Takano K | title = Amyloid fibrils from the viewpoint of protein folding | journal = Cellular and Molecular Life Sciences | volume = 61 | issue = 5 | pages = 511–524 | date = March 2004 | pmid = 15004691 | doi = 10.1007/s00018-003-3264-8 }}</ref> These fibrils deposit outside neurons in dense formations known as [[senile plaques]] or [[neuritic plaques]], in less dense aggregates as ''diffuse plaques'', and sometimes in the walls of small blood vessels in the brain in a process called [[cerebral amyloid angiopathy]].
-AD is also considered a [[tauopathy]] due to abnormal aggregation of the [[tau protein]], a [[microtubule-associated protein]] expressed in neurons that normally acts to stabilize [[microtubules]] in the cell [[cytoskeleton]]. Like most microtubule-associated proteins, tau is normally regulated by [[phosphorylation]]; however, in Alzheimer's disease, hyperphosphorylated tau accumulates as paired helical filaments<ref name="Goedert">{{cite journal |vauthors=Goedert M, Klug A, Crowther RA |title=Tau protein, the paired helical filament and Alzheimer's disease |journal=J. Alzheimer's Dis. |volume=9 |issue=3 Suppl |pages=195–207 |year=2006 |pmid=16914859 |doi=10.3233/JAD-2006-9S323}}</ref> that in turn aggregate into masses inside nerve cell bodies known as [[neurofibrillary tangles]] and as dystrophic [[neurite]]s associated with amyloid plaques. Although little is known about the process of filament assembly, it has recently been shown that a depletion of a [[prolyl isomerase]] protein in the [[parvulin]] family accelerates the accumulation of abnormal tau.<ref name="Pastorino">{{cite journal |vauthors=Pastorino L, Sun A, Lu PJ |title=The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production |journal=Nature |volume=440 |issue=7083 |pages=528–34 |year=2006 |pmid=16554819 |doi=10.1038/nature04543|bibcode = 2006Natur.440..528P |display-authors=etal}}</ref><ref name="Lim">{{cite journal |vauthors=Lim J, Lu KP |title=Pinning down phosphorylated tau and tauopathies |journal=Biochim. Biophys. Acta |volume=1739 |issue=2–3 |pages=311–22 |year=2005 |pmid=15615648 |doi=10.1016/j.bbadis.2004.10.003}}</ref>
+AD is also considered a [[tauopathy]] due to abnormal aggregation of the [[tau protein]], a [[microtubule-associated protein]] expressed in neurons that normally acts to stabilize [[microtubules]] in the cell [[cytoskeleton]]. Like most microtubule-associated proteins, tau is normally regulated by [[phosphorylation]]; however, in Alzheimer's disease, hyperphosphorylated tau accumulates as paired helical filaments<ref name="Goedert">{{cite journal | vauthors = Goedert M, Klug A, Crowther RA | title = Tau protein, the paired helical filament and Alzheimer's disease | journal = Journal of Alzheimer's Disease | volume = 9 | issue = 3 Suppl | pages = 195–207 | year = 2006 | pmid = 16914859 | doi = 10.3233/JAD-2006-9S323 }}</ref> that in turn aggregate into masses inside nerve cell bodies known as [[neurofibrillary tangles]] and as dystrophic [[neurite]]s associated with amyloid plaques. Although little is known about the process of filament assembly, it has recently been shown that a depletion of a [[prolyl isomerase]] protein in the [[parvulin]] family accelerates the accumulation of abnormal tau.<ref name="Pastorino">{{cite journal | vauthors = Pastorino L, Sun A, Lu PJ, Zhou XZ, Balastik M, Finn G, Wulf G, Lim J, Li SH, Li X, Xia W, Nicholson LK, Lu KP | display-authors = 6 | title = The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-beta production | journal = Nature | volume = 440 | issue = 7083 | pages = 528–34 | date = March 2006 | pmid = 16554819 | doi = 10.1038/nature04543 | bibcode = 2006Natur.440..528P }}</ref><ref name="Lim">{{cite journal | vauthors = Lim J, Lu KP | title = Pinning down phosphorylated tau and tauopathies | journal = Biochimica et Biophysica Acta | volume = 1739 | issue = 2-3 | pages = 311–22 | date = January 2005 | pmid = 15615648 | doi = 10.1016/j.bbadis.2004.10.003 }}</ref>
-Neuroinflammation is also involved in the complex cascade leading to AD pathology and symptoms. Considerable pathological and clinical evidence documents immunological changes associated with AD, including increased pro-inflammatory cytokine concentrations in the blood and cerebrospinal fluid.<ref name="Akiyama">{{cite journal |vauthors=Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM |title=Inflammation and Alzheimer's disease |journal=Neurobiol Aging |volume=21 |pages=383–421 |year=2000 |pmid=10858586 |doi=10.1016/S0197-4580(00)00124-X |issue=3|display-authors=etal|pmc=3887148 }}</ref><ref name="Swardfager">{{cite journal |vauthors=Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N |title=A meta-analysis of cytokines in Alzheimer's disease |journal=Biol Psychiatry |volume=68 |issue=10 |pages=930–941 |year=2010 |pmid=20692646 |doi=10.1016/j.biopsych.2010.06.012}}</ref> Whether these changes may be a cause or consequence of AD remains to be fully understood, but inflammation within the brain, including increased reactivity of the resident [[microglia]] towards amyloid deposits, has been implicated in the pathogenesis and progression of AD.<ref name="Vasefi">{{cite journal |vauthors=Vasefi M, Hudson M, Ghaboolian-Zare E |title=Diet Associated with Inflammation and Alzheimer's Disease |journal=J Alzheimers Dis Rep |volume=3 |issue=1 |pages=299–309 |date=November 2019 |pmid=31867568 |pmc=6918878 |doi=10.3233/ADR-190152 |url=}}</ref>
+Neuroinflammation is also involved in the complex cascade leading to AD pathology and symptoms. Considerable pathological and clinical evidence documents immunological changes associated with AD, including increased pro-inflammatory cytokine concentrations in the blood and cerebrospinal fluid.<ref name="Akiyama">{{cite journal | vauthors = Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T | display-authors = 6 | title = Inflammation and Alzheimer's disease | journal = Neurobiology of Aging | volume = 21 | issue = 3 | pages = 383–421 | year = 2000 | pmid = 10858586 | pmc = 3887148 | doi = 10.1016/S0197-4580(00)00124-X }}</ref><ref name="Swardfager">{{cite journal | vauthors = Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N | title = A meta-analysis of cytokines in Alzheimer's disease | journal = Biological Psychiatry | volume = 68 | issue = 10 | pages = 930–41 | date = November 2010 | pmid = 20692646 | doi = 10.1016/j.biopsych.2010.06.012 }}</ref> Whether these changes may be a cause or consequence of AD remains to be fully understood, but inflammation within the brain, including increased reactivity of the resident [[microglia]] towards amyloid deposits, has been implicated in the pathogenesis and progression of AD.<ref name="Vasefi">{{cite journal | vauthors = Vasefi M, Hudson M, Ghaboolian-Zare E | title = Diet Associated with Inflammation and Alzheimer's Disease | journal = Journal of Alzheimer's Disease Reports | volume = 3 | issue = 1 | pages = 299–309 | date = November 2019 | pmid = 31867568 | pmc = 6918878 | doi = 10.3233/ADR-190152 }}</ref>
 ==Neuropathology==
-At a [[macroscopic]] level, AD is characterized by loss of [[neuron]]s and [[synapse]]s in the [[cerebral cortex]] and certain subcortical regions. This results in gross [[atrophy]] of the affected regions, including degeneration in the [[temporal lobe]] and [[parietal lobe]], and parts of the [[frontal cortex]] and [[cingulate gyrus]].<ref name="pmid12934968">{{cite journal |author=Wenk GL |title=Neuropathologic changes in Alzheimer's disease |journal=J Clin Psychiatry |volume=64 Suppl 9 |pages=7–10 |year=2003 |pmid=12934968 }}</ref>
+At a [[macroscopic]] level, AD is characterized by loss of [[neuron]]s and [[synapse]]s in the [[cerebral cortex]] and certain subcortical regions. This results in gross [[atrophy]] of the affected regions, including degeneration in the [[temporal lobe]] and [[parietal lobe]], and parts of the [[frontal cortex]] and [[cingulate gyrus]].<ref name="pmid12934968">{{cite journal | vauthors = Wenk GL | title = Neuropathologic changes in Alzheimer's disease | journal = The Journal of Clinical Psychiatry | volume = 64 Suppl 9 | pages = 7–10 | year = 2003 | pmid = 12934968 }}</ref>
-Both [[amyloid plaques]] and [[neurofibrillary tangle]]s are clearly visible by [[microscopy]] in AD brains.<ref name="Tiraboschi">{{cite journal |vauthors=Tiraboschi P, Hansen L, Thal L, Corey-Bloom J | title = The importance of neuritic plaques and tangles to the development and evolution of AD | journal = Neurology | volume = 62 | issue = 11 | pages = 1984–9 | year = 2004 | pmid = 15184601 | doi = 10.1212/01.WNL.0000129697.01779.0A}}</ref> Plaques are dense, mostly [[insoluble]] deposits of [[protein]] and [[Cell (biology)|cellular]] material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.<ref name="pmid8038565">{{cite journal |vauthors=Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH |title=Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital |journal=Cereb. Cortex |volume=4 |issue=2 |pages=138–50 |year=1994 |pmid=8038565 |doi=10.1093/cercor/4.2.138|url=http://doc.rero.ch/record/299447/files/4-2-138.pdf }}</ref>
+Both [[amyloid plaques]] and [[neurofibrillary tangle]]s are clearly visible by [[microscopy]] in AD brains.<ref name="Tiraboschi">{{cite journal | vauthors = Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J | title = The importance of neuritic plaques and tangles to the development and evolution of AD | journal = Neurology | volume = 62 | issue = 11 | pages = 1984–9 | date = June 2004 | pmid = 15184601 | doi = 10.1212/01.WNL.0000129697.01779.0A }}</ref> Plaques are dense, mostly [[insoluble]] deposits of [[protein]] and [[Cell (biology)|cellular]] material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.<ref name="pmid8038565">{{cite journal | vauthors = Bouras C, Hof PR, Giannakopoulos P, Michel JP, Morrison JH | title = Regional distribution of neurofibrillary tangles and senile plaques in the cerebral cortex of elderly patients: a quantitative evaluation of a one-year autopsy population from a geriatric hospital | journal = Cerebral Cortex | volume = 4 | issue = 2 | pages = 138–50 | year = 1994 | pmid = 8038565 | doi = 10.1093/cercor/4.2.138 }}</ref>
 ==Biochemical characteristics==
-Fundamental to the understanding of Alzheimer's disease is the biochemical events that leads to accumulation of the amyloid-beta and tau-protein. A delicate balance of the enzymes [[secretase]]s regulate the amyloid-beta accumulation. Alpha Secretase can render a non-pathological (non-amyloidogenic) Amyloid Beta (DOI: 10.2174/156720512799361655). Recently, a link between cholinergic neuronal activity and the activity of alpha-secretase has been highlighted,<ref>{{cite journal | author = Baig AM | year = 2018 | title = Connecting the Dots: Linking the Biochemical to Morphological Transitions in Alzheimer's Disease | journal = ACS Chem Neurosci | volume =  10| pages =  21–24| doi = 10.1021/acschemneuro.8b00409 | pmid = 30160095 | doi-access = free }}</ref> which can discourage Amyloid-beta proteins deposition in brain of patients with Alzheimer's Disease.
+Fundamental to the understanding of Alzheimer's disease is the biochemical events that leads to accumulation of the amyloid-beta and tau-protein. A delicate balance of the enzymes [[secretase]]s regulate the amyloid-beta accumulation. Alpha Secretase can render a non-pathological (non-amyloidogenic) Amyloid Beta (DOI: 10.2174/156720512799361655). Recently, a link between cholinergic neuronal activity and the activity of alpha-secretase has been highlighted,<ref>{{cite journal | vauthors = Baig AM | title = Connecting the Dots: Linking the Biochemical to Morphological Transitions in Alzheimer's Disease | journal = ACS Chemical Neuroscience | volume = 10 | issue = 1 | pages = 21–24 | date = January 2019 | pmid = 30160095 | doi = 10.1021/acschemneuro.8b00409 | doi-access = free }}</ref> which can discourage Amyloid-beta proteins deposition in brain of patients with Alzheimer's Disease.
-Alzheimer's disease has been identified as a [[protein folding|protein misfolding]] disease, or [[proteopathy]], due to the accumulation of abnormally folded Amyloid-beta proteins in the brains of AD patients.<ref name="Hashimoto"/> Abnormal amyloid-beta accumulation can first be detected using cerebrospinal fluid analysis and later using positron emission tomography (PET).<ref name="Palmqvist">{{cite journal|last1=Palmqvist|first1=Sebastian|title=Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography, 2016 Apr; 139(4)|journal=Brain|doi=10.1093/brain/aww015|pmid=26936941|volume=139|issue=Pt 4|pmc=4806222|year=2016|pages=1226–36}}</ref>
+Alzheimer's disease has been identified as a [[protein folding|protein misfolding]] disease, or [[proteopathy]], due to the accumulation of abnormally folded Amyloid-beta proteins in the brains of AD patients.<ref name="Hashimoto"/> Abnormal amyloid-beta accumulation can first be detected using cerebrospinal fluid analysis and later using positron emission tomography (PET).<ref name="Palmqvist">{{cite journal | vauthors = Palmqvist S, Mattsson N, Hansson O | title = Cerebrospinal fluid analysis detects cerebral amyloid-β accumulation earlier than positron emission tomography | journal = Brain | volume = 139 | issue = Pt 4 | pages = 1226–36 | date = April 2016 | pmid = 26936941 | pmc = 4806222 | doi = 10.1093/brain/aww015 }}</ref>
-Although AD shares pathophysiological mechanisms with prion diseases, it is not transmissible like prion diseases.<ref name="Castellani">{{cite journal |vauthors=Castellni RJ, Perry G, Smith MA | title = Prion disease and Alzheimer's disease: pathogenic overlap | journal = Acta Neurobiol Exp (Wars)| year = 2004 | pmid = 15190676 | volume=64 | issue = 1 | pages=11–7}}</ref> Amyloid-beta, also written Aβ, is a short [[peptide]] that is a [[proteolysis|proteolytic]] byproduct of the [[transmembrane protein]] [[amyloid precursor protein]] (APP), whose function is unclear but thought to be involved in neuronal development. The [[presenilin]]s are components of a proteolytic complex involved in APP processing and degradation.<ref name="Cai"/>
+Although AD shares pathophysiological mechanisms with prion diseases, it is not transmissible like prion diseases.<ref name="Castellani">{{cite journal | vauthors = Castellani RJ, Perry G, Smith MA | title = Prion disease and Alzheimer's disease: pathogenic overlap | journal = Acta Neurobiologiae Experimentalis | volume = 64 | issue = 1 | pages = 11–7 | year = 2004 | pmid = 15190676 }}</ref> Amyloid-beta, also written Aβ, is a short [[peptide]] that is a [[proteolysis|proteolytic]] byproduct of the [[transmembrane protein]] [[amyloid precursor protein]] (APP), whose function is unclear but thought to be involved in neuronal development. The [[presenilin]]s are components of a proteolytic complex involved in APP processing and degradation.<ref name="Cai"/>
 Although amyloid beta [[monomer]]s are harmless, they undergo a dramatic [[conformational change]] at sufficiently high concentration to form a [[beta sheet]]-rich [[tertiary structure]] that aggregates to form [[amyloid|amyloid fibrils]]<ref name="Ohnishi"/> that deposit outside neurons in dense formations known as ''senile plaques'' or ''neuritic plaques'', in less dense aggregates as ''diffuse plaques'', and sometimes in the walls of small blood vessels in the brain in a process called amyloid angiopathy or [[congophilic angiopathy]].
@@ Line 25: / Line 25: @@
 == Potential disease mechanisms ==
-While the gross histological features of AD in the brain have been well characterized, several different hypotheses have been advanced regarding the primary cause. Among the oldest hypotheses is the [[cholinergic]] hypothesis, which suggests that deficiency in cholinergic signaling initiates the progression of the disease<ref>{{cite journal |last1=Francis |first1=P. T |last2=Palmer |first2=A. M |last3=Snape |first3=M. |last4=Wilcock |first4=G. K |title=The cholinergic hypothesis of Alzheimer's disease: a review of progress |journal=Journal of Neurology, Neurosurgery & Psychiatry |date=1 February 1999 |volume=66 |issue=2 |pages=137–147 |doi=10.1136/jnnp.66.2.137}}</ref>. Other hypotheses suggest that either misfolding tau protein inside the cell or aggregation of amyloid beta outside the cell initiates the cascade leading to AD pathology<ref>{{cite journal |last1=Tanzi |first1=Rudolph E. |last2=Bertram |first2=Lars |title=Twenty Years of the Alzheimer’s Disease Amyloid Hypothesis: A Genetic Perspective |journal=Cell |date=February 2005 |volume=120 |issue=4 |pages=545–555 |doi=doi.org/10.1016/j.cell.2005.02.008}}</ref><ref>{{cite journal |last1=Mohandas |first1=E |last2=Rajmohan |first2=V |last3=Raghunath |first3=B |title=Neurobiology of Alzheimer′s disease |journal=Indian Journal of Psychiatry |date=2009 |volume=51 |issue=1 |pages=55 |doi=10.4103/0019-5545.44908}}</ref>>.  Still other hypotheses propose metabolic factors<ref>{{cite journal |last1=Morgen |first1=Katrin |last2=Frölich |first2=Lutz |title=The metabolism hypothesis of Alzheimer’s disease: from the concept of central insulin resistance and associated consequences to insulin therapy |journal=Journal of Neural Transmission |date=April 2015 |volume=122 |issue=4 |pages=499–504 |doi=10.1007/s00702-015-1377-5}}</ref>, vascular disturbance<ref>{{cite journal |last1=de la Torre |first1=J.C. |last2=Mussivan |first2=T. |title=Can disturbed brain microcirculation cause Alzheimer’s disease? |journal=Neurological Research |date=June 1993 |volume=15 |issue=3 |pages=146–153 |doi=10.1080/01616412.1993.11740127}}</ref>, or chronically elevated inflammation in the brain<ref>{{cite journal |last1=Agostinho |first1=Paula |last2=A. Cunha |first2=Rodrigo |last3=Oliveira |first3=Catarina |title=Neuroinflammation, Oxidative Stress and the Pathogenesis of Alzheimers Disease |journal=Current Pharmaceutical Design |date=1 August 2010 |volume=16 |issue=25 |pages=2766–2778 |doi=10.2174/138161210793176572}}</ref> as the primary cause for AD. While researchers have not identified a clear causative pathway originating from any of the molecular hypothesis that explains the gross anatomical changes observed in advanced AD, variants of the amyloid beta hypothesis of molecular initiation have become dominant among many researchers to date<ref>{{cite journal |last1=Makin |first1=Simon |title=The amyloid hypothesis on trial |journal=Nature |date=July 2018 |volume=559 |issue=7715 |pages=S4–S7 |doi=10.1038/d41586-018-05719-4}}</ref>
+While the gross histological features of AD in the brain have been well characterized, several different hypotheses have been advanced regarding the primary cause. Among the oldest hypotheses is the [[cholinergic]] hypothesis, which suggests that deficiency in cholinergic signaling initiates the progression of the disease<ref>{{cite journal | vauthors = Francis PT, Palmer AM, Snape M, Wilcock GK | title = The cholinergic hypothesis of Alzheimer's disease: a review of progress | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 66 | issue = 2 | pages = 137–47 | date = February 1999 | pmid = 10071091 | doi = 10.1136/jnnp.66.2.137 }}</ref>. Other hypotheses suggest that either misfolding tau protein inside the cell or aggregation of amyloid beta outside the cell initiates the cascade leading to AD pathology<ref>{{cite journal | vauthors = Tanzi RE, Bertram L | title = Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective | journal = Cell | volume = 120 | issue = 4 | pages = 545–55 | date = February 2005 | pmid = 15734686 | doi = doi.org/10.1016/j.cell.2005.02.008 }}</ref><ref>{{cite journal | vauthors = Mohandas E, Rajmohan V, Raghunath B | title = Neurobiology of Alzheimer's disease | journal = Indian Journal of Psychiatry | volume = 51 | issue = 1 | pages = 55–61 | date = January 2009 | pmid = 19742193 | doi = 10.4103/0019-5545.44908 }}</ref>>.  Still other hypotheses propose metabolic factors<ref>{{cite journal | vauthors = Morgen K, Frölich L | title = The metabolism hypothesis of Alzheimer's disease: from the concept of central insulin resistance and associated consequences to insulin therapy | journal = Journal of Neural Transmission | volume = 122 | issue = 4 | pages = 499–504 | date = April 2015 | pmid = 25673434 | doi = 10.1007/s00702-015-1377-5 }}</ref>, vascular disturbance<ref>{{cite journal | vauthors = de la Torre JC, Mussivand T | title = Can disturbed brain microcirculation cause Alzheimer's disease? | journal = Neurological Research | volume = 15 | issue = 3 | pages = 146–53 | date = June 1993 | pmid = 8103579 | doi = 10.1080/01616412.1993.11740127 }}</ref>, or chronically elevated inflammation in the brain<ref>{{cite journal | vauthors = Agostinho P, Cunha RA, Oliveira C | title = Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease | journal = Current Pharmaceutical Design | volume = 16 | issue = 25 | pages = 2766–78 | date = 1 August 2010 | pmid = 20698820 | doi = 10.2174/138161210793176572 }}</ref> as the primary cause for AD. While researchers have not identified a clear causative pathway originating from any of the molecular hypothesis that explains the gross anatomical changes observed in advanced AD, variants of the amyloid beta hypothesis of molecular initiation have become dominant among many researchers to date<ref>{{cite journal | vauthors = Makin S | title = The amyloid hypothesis on trial | journal = Nature | volume = 559 | issue = 7715 | pages = S4-S7 | date = July 2018 | pmid = 30046080 | doi = 10.1038/d41586-018-05719-4 }}</ref>
 ===Cholinergic hypothesis===
-The cholinergic hypothesis of AD development was first proposed in 1976 by Peter Davies and A.J.F Maloney<ref>{{Cite journal|last=Davies|first=P|date=1976-12-XX|title=SELECTIVE LOSS OF CENTRAL CHOLINERGIC NEURONS IN ALZHEIMER'S DISEASE|url=https://linkinghub.elsevier.com/retrieve/pii/S014067367691936X|journal=The Lancet|language=en|volume=308|issue=8000|pages=1403|doi=10.1016/S0140-6736(76)91936-X}}</ref>. It states that Alzheimer's begins as a deficiency in the production of [[acetylcholine]], a vital [[neurotransmitter]]. Much early therapeutic research was based on this hypothesis, including restoration of the "cholinergic nuclei". The possibility of cell-replacement therapy was investigated on the basis of this hypothesis. All of the first-generation anti-Alzheimer's medications are based on this hypothesis and work to preserve acetylcholine by inhibiting [[acetylcholinesterase]]s (enzymes that break down acetylcholine). These medications, though sometimes beneficial, have not led to a cure. In all cases, they have served to only treat symptoms of the disease and have neither halted nor reversed it. These results and other research have led to the conclusion that acetylcholine deficiencies may not be directly causal, but are a result of widespread brain tissue damage, damage so widespread that cell-replacement therapies are likely to be impractical.
+The cholinergic hypothesis of AD development was first proposed in 1976 by Peter Davies and A.J.F Maloney.<ref>{{cite journal | vauthors = Davies P, Maloney AJ | title = Selective loss of central cholinergic neurons in Alzheimer's disease | journal = Lancet | volume = 2 | issue = 8000 | pages = 1403 | date = December 1976 | pmid = 63862 | doi = 10.1016/S0140-6736(76)91936-X }}</ref> It states that Alzheimer's begins as a deficiency in the production of [[acetylcholine]], a vital [[neurotransmitter]]. Much early therapeutic research was based on this hypothesis, including restoration of the "cholinergic nuclei". The possibility of cell-replacement therapy was investigated on the basis of this hypothesis. All of the first-generation anti-Alzheimer's medications are based on this hypothesis and work to preserve acetylcholine by inhibiting [[acetylcholinesterase]]s (enzymes that break down acetylcholine). These medications, though sometimes beneficial, have not led to a cure. In all cases, they have served to only treat symptoms of the disease and have neither halted nor reversed it. These results and other research have led to the conclusion that acetylcholine deficiencies may not be directly causal, but are a result of widespread brain tissue damage, damage so widespread that cell-replacement therapies are likely to be impractical.
-More recent hypotheses center on the effects of the misfolded and aggregated proteins, amyloid beta and tau. The two positions are lightheartedly described as "ba-ptist" and "tau-ist" viewpoints in one scientific publication. Therein, it is suggested that "Tau-ists" believe that the [[tau protein]] abnormalities initiate the disease cascade, while "ba-ptists" believe that [[beta amyloid]] deposits are the causative factor in the disease.<ref name="Mudher">{{cite journal |vauthors=Mudher A, Lovestone S |title=Alzheimer's disease-do tauists and baptists finally shake hands? |journal=Trends Neurosci. |volume=25 |issue=1 |pages=22–6 |year=2002 |pmid=11801334 |doi=10.1016/S0166-2236(00)02031-2}}</ref>
+More recent hypotheses center on the effects of the misfolded and aggregated proteins, amyloid beta and tau. The two positions are lightheartedly described as "ba-ptist" and "tau-ist" viewpoints in one scientific publication. Therein, it is suggested that "Tau-ists" believe that the [[tau protein]] abnormalities initiate the disease cascade, while "ba-ptists" believe that [[beta amyloid]] deposits are the causative factor in the disease.<ref name="Mudher">{{cite journal | vauthors = Mudher A, Lovestone S | title = Alzheimer's disease-do tauists and baptists finally shake hands? | journal = Trends in Neurosciences | volume = 25 | issue = 1 | pages = 22–6 | date = January 2002 | pmid = 11801334 | doi = 10.1016/S0166-2236(00)02031-2 }}</ref>
 ===Tau hypothesis===
-The hypothesis that tau is the primary causative factor has long been grounded in the observation that deposition of amyloid plaques does not correlate well with neuron loss.<ref name="Schmitz">{{cite journal |vauthors=Schmitz C, Rutten BP, Pielen A |title=Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease |journal=Am. J. Pathol. |volume=164 |issue=4 |pages=1495–502 |date=1 April 2004|pmid=15039236 |pmc=1615337 |doi=10.1016/S0002-9440(10)63235-X|display-authors=etal}}</ref> A mechanism for neurotoxicity has been proposed based on the loss of microtubule-stabilizing tau protein that leads to the degradation of the cytoskeleton.<ref name="Gray">{{cite journal |vauthors=Gray EG, Paula-Barbosa M, Roher A |title=Alzheimer's disease: paired helical filaments and cytomembranes |journal=Neuropathol. Appl. Neurobiol. |volume=13 |issue=2 |pages=91–110 |year=1987 |pmid=3614544 |doi=10.1111/j.1365-2990.1987.tb00174.x}}</ref> However, consensus has not been reached on whether tau hyperphosphorylation precedes or is caused by the formation of the abnormal helical filament aggregates.<ref name="Mudher" /> Support for the tau hypothesis also derives from the existence of other diseases known as [[tauopathy|tauopathies]] in which the same protein is identifiably misfolded.<ref name="Williams">{{cite journal |author=Williams DR |title=Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau |journal=Internal Medicine Journal |volume=36 |issue=10 |pages=652–60 |year=2006 |pmid=16958643 |doi=10.1111/j.1445-5994.2006.01153.x}}</ref> However, a majority of researchers support the alternative hypothesis that amyloid is the primary causative agent.<ref name="Mudher" />
+The hypothesis that tau is the primary causative factor has long been grounded in the observation that deposition of amyloid plaques does not correlate well with neuron loss.<ref name="Schmitz">{{cite journal | vauthors = Schmitz C, Rutten BP, Pielen A, Schäfer S, Wirths O, Tremp G, Czech C, Blanchard V, Multhaup G, Rezaie P, Korr H, Steinbusch HW, Pradier L, Bayer TA | display-authors = 6 | title = Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease | journal = The American Journal of Pathology | volume = 164 | issue = 4 | pages = 1495–502 | date = April 2004 | pmid = 15039236 | pmc = 1615337 | doi = 10.1016/S0002-9440(10)63235-X }}</ref> A mechanism for neurotoxicity has been proposed based on the loss of microtubule-stabilizing tau protein that leads to the degradation of the cytoskeleton.<ref name="Gray">{{cite journal | vauthors = Gray EG, Paula-Barbosa M, Roher A | title = Alzheimer's disease: paired helical filaments and cytomembranes | journal = Neuropathology and Applied Neurobiology | volume = 13 | issue = 2 | pages = 91–110 | year = 1987 | pmid = 3614544 | doi = 10.1111/j.1365-2990.1987.tb00174.x }}</ref> However, consensus has not been reached on whether tau hyperphosphorylation precedes or is caused by the formation of the abnormal helical filament aggregates.<ref name="Mudher" /> Support for the tau hypothesis also derives from the existence of other diseases known as [[tauopathy|tauopathies]] in which the same protein is identifiably misfolded.<ref name="Williams">{{cite journal | vauthors = Williams DR | title = Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau | journal = Internal Medicine Journal | volume = 36 | issue = 10 | pages = 652–60 | date = October 2006 | pmid = 16958643 | doi = 10.1111/j.1445-5994.2006.01153.x }}</ref> However, a majority of researchers support the alternative hypothesis that amyloid is the primary causative agent.<ref name="Mudher" />
 ===Amyloid hypothesis===
-The amyloid hypothesis is initially compelling because the gene for the amyloid beta precursor APP is located on [[chromosome 21]], and patients with [[trisomy 21]] - better known as [[Down syndrome]] - who have an extra [[gene dosage|gene copy]] exhibit AD-like disorders by 40 years of age.<ref name="Nistor">{{cite journal |vauthors=Nistor M, Don M, Parekh M |title=Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain |journal=Neurobiol. Aging |volume=28 |issue=10 |pages=1493–506 |year=2007 |pmid=16904243 |doi=10.1016/j.neurobiolaging.2006.06.023 |pmc=3375834|display-authors=etal}}</ref><ref name="Lott">{{cite journal |vauthors=Lott IT, Head E |title=Alzheimer disease and Down syndrome: factors in pathogenesis |journal=Neurobiol. Aging |volume=26 |issue=3 |pages=383–9 |year=2005 |pmid=15639317 |doi=10.1016/j.neurobiolaging.2004.08.005}}</ref> The amyloid hypothesis points to the [[cytotoxicity]] of mature aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis and thus inducing [[apoptosis]].<ref name="Yankner">{{cite journal |vauthors=Yankner BA, Duffy LK, Kirschner DA |title=Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides |journal=Science |volume=250 |issue=4978 |pages=279–82 |year=1990 |pmid=2218531 |doi=10.1126/science.2218531|bibcode = 1990Sci...250..279Y }}</ref> This hypothesis is supported by the observation that higher levels of a variant of the beta amyloid protein known to form fibrils faster ''in vitro'' correlate with earlier onset and greater cognitive impairment in mouse models<ref name="Iijima">{{cite journal |vauthors=Iijima K, Liu HP, Chiang AS, Hearn SA, Konsolaki M, Zhong Y |title=Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue=17 |pages=6623–8 |year=2004 |pmid=15069204 |doi=10.1073/pnas.0400895101 |pmc=404095|bibcode = 2004PNAS..101.6623I }}</ref> and with AD diagnosis in humans.<ref name="Gregory">{{cite journal |vauthors=Gregory GC, Halliday GM |title=What is the dominant Abeta species in human brain tissue? A review |journal=Neurotoxicity Research |volume=7 |issue=1–2 |pages=29–41 |year=2005 |pmid=15639796 |doi=10.1007/BF03033774}}</ref> However, mechanisms for the induced calcium influx, or proposals for alternative cytotoxic mechanisms, by mature fibrils are not obvious.{{clarify|date=April 2019}}
+The amyloid hypothesis is initially compelling because the gene for the amyloid beta precursor APP is located on [[chromosome 21]], and patients with [[trisomy 21]] - better known as [[Down syndrome]] - who have an extra [[gene dosage|gene copy]] exhibit AD-like disorders by 40 years of age.<ref name="Nistor">{{cite journal | vauthors = Nistor M, Don M, Parekh M, Sarsoza F, Goodus M, Lopez GE, Kawas C, Leverenz J, Doran E, Lott IT, Hill M, Head E | display-authors = 6 | title = Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain | journal = Neurobiology of Aging | volume = 28 | issue = 10 | pages = 1493–506 | date = October 2007 | pmid = 16904243 | pmc = 3375834 | doi = 10.1016/j.neurobiolaging.2006.06.023 }}</ref><ref name="Lott">{{cite journal | vauthors = Lott IT, Head E | title = Alzheimer disease and Down syndrome: factors in pathogenesis | journal = Neurobiology of Aging | volume = 26 | issue = 3 | pages = 383–9 | date = March 2005 | pmid = 15639317 | doi = 10.1016/j.neurobiolaging.2004.08.005 }}</ref> The amyloid hypothesis points to the [[cytotoxicity]] of mature aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis and thus inducing [[apoptosis]].<ref name="Yankner">{{cite journal | vauthors = Yankner BA, Duffy LK, Kirschner DA | title = Neurotrophic and neurotoxic effects of amyloid beta protein: reversal by tachykinin neuropeptides | journal = Science | volume = 250 | issue = 4978 | pages = 279–82 | date = October 1990 | pmid = 2218531 | doi = 10.1126/science.2218531 | bibcode = 1990Sci...250..279Y }}</ref> This hypothesis is supported by the observation that higher levels of a variant of the beta amyloid protein known to form fibrils faster ''in vitro'' correlate with earlier onset and greater cognitive impairment in mouse models<ref name="Iijima">{{cite journal | vauthors = Iijima K, Liu HP, Chiang AS, Hearn SA, Konsolaki M, Zhong Y | title = Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 17 | pages = 6623–8 | date = April 2004 | pmid = 15069204 | pmc = 404095 | doi = 10.1073/pnas.0400895101 | bibcode = 2004PNAS..101.6623I }}</ref> and with AD diagnosis in humans.<ref name="Gregory">{{cite journal | vauthors = Gregory GC, Halliday GM | title = What is the dominant Abeta species in human brain tissue? A review | journal = Neurotoxicity Research | volume = 7 | issue = 1-2 | pages = 29–41 | year = 2005 | pmid = 15639796 | doi = 10.1007/BF03033774 }}</ref> However, mechanisms for the induced calcium influx, or proposals for alternative cytotoxic mechanisms, by mature fibrils are not obvious.{{clarify|date=April 2019}}
 [[File:Apomorphine therapeutic scheme.png|thumb|325px|Flow chart depicting the role of [[Apomorphine#Alzheimer's disease|apomorphine]] in Alzheimer's disease.]]
-A more recent variation of the amyloid hypothesis identifies the cytotoxic species as an intermediate misfolded form of amyloid beta, neither a soluble monomer nor a mature aggregated polymer but an [[oligomer]]ic species, possibly toroidal or star-shaped with a central channel<ref name="Blanchard1">{{cite journal |vauthors=Blanchard BJ, Hiniker AE, Lu CC, Margolin Y, Yu AS, Ingram VM |title=Elimination of Amyloid beta Neurotoxicity |journal= J. Alzheimer's Dis. |volume=2 |issue=2 |pages=137–149 |year=2000 |pmid=12214104 |doi=10.3233/JAD-2000-2214}}</ref> that may induce apoptosis by physically piercing the cell membrane.<ref name="Abramov">{{cite journal |vauthors=Abramov AY, Canevari L, Duchen MR |title=Calcium signals induced by amyloid beta peptide and their consequences in neurons and astrocytes in culture |journal=Biochim. Biophys. Acta |volume=1742 |issue=1–3 |pages=81–7 |year=2004 |pmid=15590058 |doi=10.1016/j.bbamcr.2004.09.006}}</ref> This [[Ion channel hypothesis of Alzheimer's disease|ion channel hypothesis]] postulates that oligomers of soluble, non-fibrillar Aβ form membrane ion channels allowing unregulated calcium influx into neurons.<ref>{{Cite journal|last=Arispe|first=N|last2=Rojas|first2=E|last3=Pollard|first3=H B|date=1993-01-15|title=Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum.|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=90|issue=2|pages=567–571|issn=0027-8424|pmc=45704|pmid=8380642|doi=10.1073/pnas.90.2.567|bibcode=1993PNAS...90..567A}}</ref> A related alternative suggests that a globular oligomer localized to [[dendrite|dendritic processes]] and [[axon]]s in neurons is the cytotoxic species.<ref name="Barghorn">{{cite journal |vauthors=Barghorn S, Nimmrich V, Striebinger A |title=Globular amyloid beta-peptide oligomer - a homogenous and stable neuropathological protein in Alzheimer's disease |journal=J. Neurochem. |volume=95 |issue=3 |pages=834–47 |year=2005 |pmid=16135089 |doi=10.1111/j.1471-4159.2005.03407.x|display-authors=etal|doi-access=free }}</ref><ref name="Kokubo">{{cite journal |vauthors=Kokubo H, Kayed R, Glabe CG, Yamaguchi H |title=Soluble Abeta oligomers ultrastructurally localize to cell processes and might be related to synaptic dysfunction in Alzheimer's disease brain |journal=Brain Res. |volume=1031 |issue=2 |pages=222–8 |year=2005 |pmid=15649447 |doi=10.1016/j.brainres.2004.10.041}}</ref> The prefibrillar aggregates were shown to be able to disrupt the membrane.<ref name="FlagmeierDe2017">{{cite journal|last1=Flagmeier|first1=Patrick|last2=De|first2=Suman|last3=Wirthensohn|first3=David C.|last4=Lee|first4=Steven F.|last5=Vincke|first5=Cécile|last6=Muyldermans|first6=Serge|last7=Knowles|first7=Tuomas P. J.|last8=Gandhi|first8=Sonia|last9=Dobson|first9=Christopher M.|last10=Klenerman|first10=David|title=Ultrasensitive Measurement of Ca2+ Influx into Lipid Vesicles Induced by Protein Aggregates|journal=Angewandte Chemie International Edition|volume=56|issue=27|year=2017|pages=7750–7754|issn=1433-7851|doi=10.1002/anie.201700966|pmid=28474754|pmc=5615231}}</ref>
+A more recent variation of the amyloid hypothesis identifies the cytotoxic species as an intermediate misfolded form of amyloid beta, neither a soluble monomer nor a mature aggregated polymer but an [[oligomer]]ic species, possibly toroidal or star-shaped with a central channel<ref name="Blanchard1">{{cite journal | vauthors = Blanchard BJ, Hiniker AE, Lu CC, Margolin Y, Yu AS, Ingram VM | title = Elimination of Amyloid beta Neurotoxicity | journal = Journal of Alzheimer's Disease | volume = 2 | issue = 2 | pages = 137–149 | date = June 2000 | pmid = 12214104 | doi = 10.3233/JAD-2000-2214 }}</ref> that may induce apoptosis by physically piercing the cell membrane.<ref name="Abramov">{{cite journal | vauthors = Abramov AY, Canevari L, Duchen MR | title = Calcium signals induced by amyloid beta peptide and their consequences in neurons and astrocytes in culture | journal = Biochimica et Biophysica Acta | volume = 1742 | issue = 1-3 | pages = 81–7 | date = December 2004 | pmid = 15590058 | doi = 10.1016/j.bbamcr.2004.09.006 }}</ref> This [[Ion channel hypothesis of Alzheimer's disease|ion channel hypothesis]] postulates that oligomers of soluble, non-fibrillar Aβ form membrane ion channels allowing unregulated calcium influx into neurons.<ref>{{cite journal | vauthors = Arispe N, Rojas E, Pollard HB | title = Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 2 | pages = 567–71 | date = January 1993 | pmid = 8380642 | pmc = 45704 | doi = 10.1073/pnas.90.2.567 | bibcode = 1993PNAS...90..567A }}</ref> A related alternative suggests that a globular oligomer localized to [[dendrite|dendritic processes]] and [[axon]]s in neurons is the cytotoxic species.<ref name="Barghorn">{{cite journal | vauthors = Barghorn S, Nimmrich V, Striebinger A, Krantz C, Keller P, Janson B, Bahr M, Schmidt M, Bitner RS, Harlan J, Barlow E, Ebert U, Hillen H | display-authors = 6 | title = Globular amyloid beta-peptide oligomer - a homogenous and stable neuropathological protein in Alzheimer's disease | journal = Journal of Neurochemistry | volume = 95 | issue = 3 | pages = 834–47 | date = November 2005 | pmid = 16135089 | doi = 10.1111/j.1471-4159.2005.03407.x | doi-access = free }}</ref><ref name="Kokubo">{{cite journal | vauthors = Kokubo H, Kayed R, Glabe CG, Yamaguchi H | title = Soluble Abeta oligomers ultrastructurally localize to cell processes and might be related to synaptic dysfunction in Alzheimer's disease brain | journal = Brain Research | volume = 1031 | issue = 2 | pages = 222–8 | date = January 2005 | pmid = 15649447 | doi = 10.1016/j.brainres.2004.10.041 }}</ref> The prefibrillar aggregates were shown to be able to disrupt the membrane.<ref name="FlagmeierDe2017">{{cite journal | vauthors = Flagmeier P, De S, Wirthensohn DC, Lee SF, Vincke C, Muyldermans S, Knowles TP, Gandhi S, Dobson CM, Klenerman D | display-authors = 6 | title = Ultrasensitive Measurement of Ca<sup>2+</sup> Influx into Lipid Vesicles Induced by Protein Aggregates | journal = Angewandte Chemie | volume = 56 | issue = 27 | pages = 7750–7754 | date = June 2017 | pmid = 28474754 | pmc = 5615231 | doi = 10.1002/anie.201700966 }}</ref>
-The cytotoxic-fibril hypothesis presents a clear target for drug development: inhibit the fibrillization process. Much early development work on [[lead compound]]s has focused on this inhibition;<ref name="Blanchard2">{{cite journal |vauthors=Blanchard BJ, Chen A, Rozeboom LM, Stafford KA, Weigele P, Ingram VM |title=Efficient reversal of Alzheimer's disease fibril formation and elimination of neurotoxicity by a small molecule |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue=40 |pages=14326–32 |year=2004 |pmid=15388848 |doi=10.1073/pnas.0405941101 |pmc=521943|bibcode = 2004PNAS..10114326B }}</ref><ref name="Porat">{{cite journal | doi = 10.1111/j.1747-0285.2005.00318.x |vauthors=Porat Y, Abramowitz A, Gazit E | year = 2006 | title = Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism | journal = Chem Biol Drug Des | volume = 67 | issue = 1| pages = 27–37 | pmid=16492146 | doi-access = free }}</ref><ref name="Kanapathipillai">{{cite journal |vauthors=Kanapathipillai M, Lentzen G, Sierks M, Park CB |title=Ectoine and hydroxyectoine inhibit aggregation and neurotoxicity of Alzheimer's beta-amyloid |journal=FEBS Lett. |volume=579 |issue=21 |pages=4775–80 |year=2005 |pmid=16098972 |doi=10.1016/j.febslet.2005.07.057|doi-access=free }}</ref> most are also reported to reduce neurotoxicity, but the toxic-oligomer theory would imply that prevention of oligomeric assembly is the more important process<ref name="ReferenceA">{{cite journal | vauthors = Himeno E, Ohyagi Y, Ma L, Nakamura N, Miyoshi K, Sakae N, Motomura K, Soejima N, Yamasaki R, Hashimoto T, Tabira T, LaFerla FM, Kira J | title = Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation | journal = Annals of Neurology | volume = 69 | issue = 2 | pages = 248–56 | date = February 2011 | pmid = 21387370 | doi = 10.1002/ana.22319 | url = http://www.nfomedia.com/static/nfo/1212/resources/ApomorphineAD.pdf }}</ref><ref name=lashuel>{{cite journal | vauthors = Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A, Teichberg S, Callaway DJ | title = New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease | journal = The Journal of Biological Chemistry | volume = 277 | issue = 45 | pages = 42881–90 | date = November 2002 | pmid = 12167652 | doi = 10.1074/jbc.M206593200 | doi-access = free }}</ref>
+The cytotoxic-fibril hypothesis presents a clear target for drug development: inhibit the fibrillization process. Much early development work on [[lead compound]]s has focused on this inhibition;<ref name="Blanchard2">{{cite journal | vauthors = Blanchard BJ, Chen A, Rozeboom LM, Stafford KA, Weigele P, Ingram VM | title = Efficient reversal of Alzheimer's disease fibril formation and elimination of neurotoxicity by a small molecule | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 40 | pages = 14326–32 | date = October 2004 | pmid = 15388848 | pmc = 521943 | doi = 10.1073/pnas.0405941101 | bibcode = 2004PNAS..10114326B }}</ref><ref name="Porat">{{cite journal | vauthors = Porat Y, Abramowitz A, Gazit E | title = Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism | journal = Chemical Biology & Drug Design | volume = 67 | issue = 1 | pages = 27–37 | date = January 2006 | pmid = 16492146 | doi = 10.1111/j.1747-0285.2005.00318.x | doi-access = free }}</ref><ref name="Kanapathipillai">{{cite journal | vauthors = Kanapathipillai M, Lentzen G, Sierks M, Park CB | title = Ectoine and hydroxyectoine inhibit aggregation and neurotoxicity of Alzheimer's beta-amyloid | journal = FEBS Letters | volume = 579 | issue = 21 | pages = 4775–80 | date = August 2005 | pmid = 16098972 | doi = 10.1016/j.febslet.2005.07.057 | doi-access = free }}</ref> most are also reported to reduce neurotoxicity, but the toxic-oligomer theory would imply that prevention of oligomeric assembly is the more important process<ref name="ReferenceA">{{cite journal | vauthors = Himeno E, Ohyagi Y, Ma L, Nakamura N, Miyoshi K, Sakae N, Motomura K, Soejima N, Yamasaki R, Hashimoto T, Tabira T, LaFerla FM, Kira J | display-authors = 6 | title = Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation | journal = Annals of Neurology | volume = 69 | issue = 2 | pages = 248–56 | date = February 2011 | pmid = 21387370 | doi = 10.1002/ana.22319 }}</ref><ref name=lashuel>{{cite journal | vauthors = Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A, Teichberg S, Callaway DJ | title = New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease | journal = The Journal of Biological Chemistry | volume = 277 | issue = 45 | pages = 42881–90 | date = November 2002 | pmid = 12167652 | doi = 10.1074/jbc.M206593200 | doi-access = free }}</ref>
-<ref name="Lee">{{cite journal |vauthors=Lee KH, Shin BH, Shin KJ, Kim DJ, Yu J |title=A hybrid molecule that prohibits amyloid fibrils and alleviates neuronal toxicity induced by beta-amyloid (1-42) |journal=Biochem. Biophys. Res. Commun. |volume=328 |issue=4 |pages=816–23 |year=2005 |pmid=15707952 |doi=10.1016/j.bbrc.2005.01.030}}</ref> or that a better target lies upstream, for example in the inhibition of APP processing to amyloid beta.<ref name="Espeseth">{{cite journal |vauthors=Espeseth AS, Xu M, Huang Q |title=Compounds that bind APP and inhibit Abeta processing in vitro suggest a novel approach to Alzheimer disease therapeutics |journal=J. Biol. Chem. |volume=280 |issue=18 |pages=17792–7 |year=2005 |pmid=15737955 |doi=10.1074/jbc.M414331200 |display-authors=etal|doi-access=free }}</ref>  For example, [[apomorphine]] was seen to significantly improve memory function through the increased successful completion of the [[Morris water navigation task|Morris Water Maze]].<ref name=ReferenceA />
+<ref name="Lee">{{cite journal | vauthors = Lee KH, Shin BH, Shin KJ, Kim DJ, Yu J | title = A hybrid molecule that prohibits amyloid fibrils and alleviates neuronal toxicity induced by beta-amyloid (1-42) | journal = Biochemical and Biophysical Research Communications | volume = 328 | issue = 4 | pages = 816–23 | date = March 2005 | pmid = 15707952 | doi = 10.1016/j.bbrc.2005.01.030 }}</ref> or that a better target lies upstream, for example in the inhibition of APP processing to amyloid beta.<ref name="Espeseth">{{cite journal | vauthors = Espeseth AS, Xu M, Huang Q, Coburn CA, Jones KL, Ferrer M, Zuck PD, Strulovici B, Price EA, Wu G, Wolfe AL, Lineberger JE, Sardana M, Tugusheva K, Pietrak BL, Crouthamel MC, Lai MT, Dodson EC, Bazzo R, Shi XP, Simon AJ, Li Y, Hazuda DJ | display-authors = 6 | title = Compounds that bind APP and inhibit Abeta processing in vitro suggest a novel approach to Alzheimer disease therapeutics | journal = The Journal of Biological Chemistry | volume = 280 | issue = 18 | pages = 17792–7 | date = May 2005 | pmid = 15737955 | doi = 10.1074/jbc.M414331200 | doi-access = free }}</ref>  For example, [[apomorphine]] was seen to significantly improve memory function through the increased successful completion of the [[Morris water navigation task|Morris Water Maze]].<ref name=ReferenceA />
 ;Soluble intracellular (o)Aβ42
 Two papers have shown that oligomeric (o)Aβ42 (a species of Aβ), in soluble intracellular form, acutely inhibits [[synaptic transmission]], a pathophysiology that characterizes AD (in its early stages), by activating [[casein kinase 2]].<ref>
-{{Cite journal| last7 = Sugimori | journal = Proceedings of the National Academy of Sciences of the United States of America | volume =  106 | first8 = R. | title = Synaptic transmission block by presynaptic injection of oligomeric amyloid beta| issue =  14| pages =  5901–5906| pmid = 19304802 | pmc = 2659170 | doi = 10.1073/pnas.0900944106| last1 = Moreno| issn = 0027-8424 | date=Mar 2009 | first7 = M. | first2 = E.| last5 = Kim | first3 = G.| last2 = Yu| last4 = Hernandez | first1 = H. | first4 = I.| last6 = Moreira| last8 = Llinás | first6 = E. | first5 = N.| last3 = Pigino|bibcode = 2009PNAS..106.5901M }}</ref><ref>
+{{cite journal | vauthors = Moreno H, Yu E, Pigino G, Hernandez AI, Kim N, Moreira JE, Sugimori M, Llinás RR | display-authors = 6 | title = Synaptic transmission block by presynaptic injection of oligomeric amyloid beta | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 14 | pages = 5901–6 | date = April 2009 | pmid = 19304802 | pmc = 2659170 | doi = 10.1073/pnas.0900944106 | bibcode = 2009PNAS..106.5901M }}</ref><ref>
-{{Cite journal| last3 = Atagi| first1 = G. | first2 = G.| last2 = Morfini| last1 = Pigino | first3 = Y.| last7 = Ladu | first4 = A.| last9 = Brady| last4 = Deshpande | first5 = C.| last5 = Yu| last8 = Busciglio | first6 = L.| last6 = Jungbauer | first7 = M. | first8 = J. | first9 = S. | title = Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta | journal = Proceedings of the National Academy of Sciences of the United States of America | volume =  106| issue =  14| pages =  5907–5912 | date=Mar 2009 | issn = 0027-8424| pmid = 19321417| pmc = 2667037 | doi = 10.1073/pnas.0901229106|bibcode = 2009PNAS..106.5907P }}</ref>
+{{cite journal | vauthors = Pigino G, Morfini G, Atagi Y, Deshpande A, Yu C, Jungbauer L, LaDu M, Busciglio J, Brady S | display-authors = 6 | title = Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 14 | pages = 5907–12 | date = April 2009 | pmid = 19321417 | pmc = 2667037 | doi = 10.1073/pnas.0901229106 | bibcode = 2009PNAS..106.5907P }}</ref>
 === Inflammatory Hypothesis ===
-Converging evidence suggests/supports that a sustained inflammatory response in the brain is a core feature of AD pathology and may be a key factor in AD pathogenesis<ref>{{Cite journal|last=Kinney|first=Jefferson W.|last2=Bemiller|first2=Shane M.|last3=Murtishaw|first3=Andrew S.|last4=Leisgang|first4=Amanda M.|last5=Salazar|first5=Arnold M.|last6=Lamb|first6=Bruce T.|date=2018-01-XX|title=Inflammation as a central mechanism in Alzheimer's disease|url=https://onlinelibrary.wiley.com/doi/abs/10.1016/j.trci.2018.06.014|journal=Alzheimer's & Dementia: Translational Research & Clinical Interventions|language=en|volume=4|issue=1|pages=575–590|doi=10.1016/j.trci.2018.06.014|issn=2352-8737|pmc=PMC6214864|pmid=30406177}}</ref><ref>{{Cite journal|last=T. Griffin|first=W. Sue|last2=Sheng|first2=Jin Gen|last3=Roberts|first3=Gareth W.|last4=Mrak|first4=Robert E.|date=1995-03-XX|title=Interleukin-1 Expression in Different Plaque Types in Alzheimerʼs Disease: Significance in Plaque Evalution|url=https://academic.oup.com/jnen/article-lookup/doi/10.1097/00005072-199503000-00014|journal=Journal of Neuropathology and Experimental Neurology|language=en|volume=54|issue=2|pages=276–281|doi=10.1097/00005072-199503000-00014|issn=0022-3069}}</ref>. The brains of AD patients exhibit several markers of increased inflammatory signaling<ref>{{Cite journal|last=Griffin|first=W. S.|last2=Stanley|first2=L. C.|last3=Ling|first3=C.|last4=White|first4=L.|last5=MacLeod|first5=V.|last6=Perrot|first6=L. J.|last7=White|first7=C. L.|last8=Araoz|first8=C.|date=1989-10-01|title=Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease.|url=http://www.pnas.org/cgi/doi/10.1073/pnas.86.19.7611|journal=Proceedings of the National Academy of Sciences|language=en|volume=86|issue=19|pages=7611–7615|doi=10.1073/pnas.86.19.7611|issn=0027-8424|pmc=PMC298116|pmid=2529544}}</ref><ref>{{Cite journal|last=Gomez-Nicola|first=Diego|last2=Boche|first2=Delphine|date=2015-12-XX|title=Post-mortem analysis of neuroinflammatory changes in human Alzheimer’s disease|url=http://alzres.com/content/7/1/42|journal=Alzheimer's Research & Therapy|language=en|volume=7|issue=1|pages=42|doi=10.1186/s13195-015-0126-1|issn=1758-9193|pmc=PMC4405851|pmid=25904988}}</ref><ref>{{Cite journal|last=Knezevic|first=Dunja|last2=Mizrahi|first2=Romina|date=2018-01-XX|title=Molecular imaging of neuroinflammation in Alzheimer's disease and mild cognitive impairment|url=https://linkinghub.elsevier.com/retrieve/pii/S027858461730060X|journal=Progress in Neuro-Psychopharmacology and Biological Psychiatry|language=en|volume=80|pages=123–131|doi=10.1016/j.pnpbp.2017.05.007}}</ref>. The inflammatory hypothesis proposes that chronically elevated inflammation in the brain is a crucial component to the amyloid cascade<ref>{{Cite journal|last=McGeer|first=Patrick L.|last2=McGeer|first2=Edith G.|date=2013-10-XX|title=The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy|url=http://link.springer.com/10.1007/s00401-013-1177-7|journal=Acta Neuropathologica|language=en|volume=126|issue=4|pages=479–497|doi=10.1007/s00401-013-1177-7|issn=0001-6322}}</ref> in the early phases of AD and magnifies disease severity in later stages of AD. Aβ is present in healthy brains and serves a vital physiological function in recovery from neuronal injury, protection from infection, and repair of the blood-brain barrier<ref>{{Cite journal|last=Brothers|first=Holly M.|last2=Gosztyla|first2=Maya L.|last3=Robinson|first3=Stephen R.|date=2018-04-25|title=The Physiological Roles of Amyloid-β Peptide Hint at New Ways to Treat Alzheimer's Disease|url=http://journal.frontiersin.org/article/10.3389/fnagi.2018.00118/full|journal=Frontiers in Aging Neuroscience|volume=10|pages=118|doi=10.3389/fnagi.2018.00118|issn=1663-4365|pmc=PMC5996906|pmid=29922148}}</ref>, however it is unknown how Aβ production starts to exceed the clearance capacity of the brain and initiates AD progression. A possible explanation is that Aβ causes microglia, the resident immune cell of the brain, to become activated  and secrete pro-inflammatory signaling molecules, called cytokines, which recruit other local microglia<ref>{{Cite journal|last=Kreisl|first=William C.|date=2017-07-XX|title=Discerning the relationship between microglial activation and Alzheimer’s disease|url=https://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awx151|journal=Brain|language=en|volume=140|issue=7|pages=1825–1828|doi=10.1093/brain/awx151|issn=0006-8950}}</ref>. While acute microglial activation, as in response to injury, is beneficial and allows microglia to clear Aβ and other cellular debris via phagocytosis, chronically activated microglia exhibit decreased efficiency in Aβ clearance<ref>{{Cite journal|last=Kinney|first=Jefferson W.|last2=Bemiller|first2=Shane M.|last3=Murtishaw|first3=Andrew S.|last4=Leisgang|first4=Amanda M.|last5=Salazar|first5=Arnold M.|last6=Lamb|first6=Bruce T.|date=2018-01-XX|title=Inflammation as a central mechanism in Alzheimer's disease|url=https://onlinelibrary.wiley.com/doi/abs/10.1016/j.trci.2018.06.014|journal=Alzheimer's & Dementia: Translational Research & Clinical Interventions|language=en|volume=4|issue=1|pages=575–590|doi=10.1016/j.trci.2018.06.014|issn=2352-8737|pmc=PMC6214864|pmid=30406177}}</ref>. Despite this reduced AB clearance capacity, activated microglia continue to secrete pro-inflammatory cytokines like interleukins 1β and 6 (IL-6, IL-1β) and tumor necrosis factor-alpha (TNF-a), as well as reactive oxygen species which disrupt healthy synaptic functioning<ref>{{Cite journal|last=Agostinho|first=Paula|last2=A. Cunha|first2=Rodrigo|last3=Oliveira|first3=Catarina|date=2010-08-01|title=Neuroinflammation, Oxidative Stress and the Pathogenesis of Alzheimers Disease|url=http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1381-6128&volume=16&issue=25&spage=2766|journal=Current Pharmaceutical Design|language=en|volume=16|issue=25|pages=2766–2778|doi=10.2174/138161210793176572}}</ref> and eventually cause neuronal death<ref>{{Cite journal|last=Wang|first=Wen-Ying|last2=Tan|first2=Meng-Shan|last3=Yu|first3=Jin-Tai|last4=Tan|first4=Lan|date=2015/06|title=Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease|url=https://atm.amegroups.com/article/view/6546|journal=Annals of Translational Medicine|language=en|volume=3|issue=10|pages=7–7|doi=10.3978/j.issn.2305-5839.2015.03.49|issn=2305-5847|pmc=PMC4486922|pmid=26207229}}</ref>. The loss of synaptic functioning and later neuronal death is responsible for the cognitive impairments and loss of volume in key brain regions which are associated with AD<ref>{{Cite journal|last=Akiyama|first=Haruhiko|last2=Barger|first2=Steven|last3=Barnum|first3=Scott|last4=Bradt|first4=Bonnie|last5=Bauer|first5=Joachim|last6=Cole|first6=Greg M.|last7=Cooper|first7=Neil R.|last8=Eikelenboom|first8=Piet|last9=Emmerling|first9=Mark|last10=Fiebich|first10=Berndt L.|last11=Finch|first11=Caleb E.|date=2000|title=Inflammation and Alzheimer’s disease|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3887148/|journal=Neurobiology of aging|volume=21|issue=3|pages=383–421|issn=0197-4580|pmc=3887148|pmid=10858586}}</ref>. IL-1B, IL-6, and TNF-a cause further production of Aβ oligomers, as well as tau hyperphosphorylation, leading to continued microglia activation and creating a feed forward mechanism in which Aβ production is increased and Aβ clearance is decreased eventually causing the formation of Aβ plaques<ref>{{Cite journal|date=2005-02-01|title=The role of inflammation in Alzheimer's disease|url=https://www.sciencedirect.com/science/article/abs/pii/S1357272504002699|journal=The International Journal of Biochemistry & Cell Biology|language=en|volume=37|issue=2|pages=289–305|doi=10.1016/j.biocel.2004.07.009|issn=1357-2725}}</ref><ref>{{Cite journal|last=Meraz-Ríos|first=Marco A.|last2=Toral-Rios|first2=Danira|last3=Franco-Bocanegra|first3=Diana|last4=Villeda-Hernández|first4=Juana|last5=Campos-Peña|first5=Victoria|date=2013|title=Inflammatory process in Alzheimer's Disease|url=http://journal.frontiersin.org/article/10.3389/fnint.2013.00059/abstract|journal=Frontiers in Integrative Neuroscience|volume=7|doi=10.3389/fnint.2013.00059|issn=1662-5145|pmc=PMC3741576|pmid=23964211}}</ref>.
+Converging evidence suggests/supports that a sustained inflammatory response in the brain is a core feature of AD pathology and may be a key factor in AD pathogenesis<ref>{{cite journal | vauthors = Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT | title = Inflammation as a central mechanism in Alzheimer's disease | journal = Alzheimer's & Dementia | volume = 4 | issue = 1 | pages = 575–590 | date = 2018-01-XX | pmid = 30406177 | pmc = 6214864 | doi = 10.1016/j.trci.2018.06.014 }}</ref><ref>{{cite journal | vauthors = Griffin WS, Sheng JG, Roberts GW, Mrak RE | title = Interleukin-1 expression in different plaque types in Alzheimer's disease: significance in plaque evolution | journal = Journal of Neuropathology and Experimental Neurology | volume = 54 | issue = 2 | pages = 276–81 | date = March 1995 | pmid = 7876895 | doi = 10.1097/00005072-199503000-00014 }}</ref>. The brains of AD patients exhibit several markers of increased inflammatory signaling<ref>{{cite journal | vauthors = Griffin WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White CL, Araoz C | display-authors = 6 | title = Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 19 | pages = 7611–5 | date = October 1989 | pmid = 2529544 | pmc = 298116 | doi = 10.1073/pnas.86.19.7611 }}</ref><ref>{{cite journal | vauthors = Gomez-Nicola D, Boche D | title = Post-mortem analysis of neuroinflammatory changes in human Alzheimer's disease | journal = Alzheimer's Research & Therapy | volume = 7 | issue = 1 | pages = 42 | date = 2015-12-XX | pmid = 25904988 | pmc = 4405851 | doi = 10.1186/s13195-015-0126-1 }}</ref><ref>{{cite journal | vauthors = Knezevic D, Mizrahi R | title = Molecular imaging of neuroinflammation in Alzheimer's disease and mild cognitive impairment | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 80 | issue = Pt B | pages = 123–131 | date = January 2018 | pmid = 28533150 | doi = 10.1016/j.pnpbp.2017.05.007 }}</ref>. The inflammatory hypothesis proposes that chronically elevated inflammation in the brain is a crucial component to the amyloid cascade<ref>{{cite journal | vauthors = McGeer PL, McGeer EG | title = The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy | journal = Acta Neuropathologica | volume = 126 | issue = 4 | pages = 479–97 | date = October 2013 | pmid = 24052108 | doi = 10.1007/s00401-013-1177-7 }}</ref> in the early phases of AD and magnifies disease severity in later stages of AD. Aβ is present in healthy brains and serves a vital physiological function in recovery from neuronal injury, protection from infection, and repair of the blood-brain barrier<ref>{{cite journal | vauthors = Brothers HM, Gosztyla ML, Robinson SR | title = The Physiological Roles of Amyloid-β Peptide Hint at New Ways to Treat Alzheimer's Disease | journal = Frontiers in Aging Neuroscience | volume = 10 | pages = 118 | date = 2018-04-25 | pmid = 29922148 | pmc = 5996906 | doi = 10.3389/fnagi.2018.00118 }}</ref>, however it is unknown how Aβ production starts to exceed the clearance capacity of the brain and initiates AD progression. A possible explanation is that Aβ causes microglia, the resident immune cell of the brain, to become activated  and secrete pro-inflammatory signaling molecules, called cytokines, which recruit other local microglia<ref>{{cite journal | vauthors = Kreisl WC | title = Discerning the relationship between microglial activation and Alzheimer's disease | journal = Brain | volume = 140 | issue = 7 | pages = 1825–1828 | date = July 2017 | pmid = 29177498 | doi = 10.1093/brain/awx151 }}</ref>. While acute microglial activation, as in response to injury, is beneficial and allows microglia to clear Aβ and other cellular debris via phagocytosis, chronically activated microglia exhibit decreased efficiency in Aβ clearance<ref>{{cite journal | vauthors = Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT | title = Inflammation as a central mechanism in Alzheimer's disease | journal = Alzheimer's & Dementia | volume = 4 | issue = 1 | pages = 575–590 | date = 2018-01-XX | pmid = 30406177 | pmc = 6214864 | doi = 10.1016/j.trci.2018.06.014 }}</ref>. Despite this reduced AB clearance capacity, activated microglia continue to secrete pro-inflammatory cytokines like interleukins 1β and 6 (IL-6, IL-1β) and tumor necrosis factor-alpha (TNF-a), as well as reactive oxygen species which disrupt healthy synaptic functioning<ref>{{cite journal | vauthors = Agostinho P, Cunha RA, Oliveira C | title = Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease | journal = Current Pharmaceutical Design | volume = 16 | issue = 25 | pages = 2766–78 | date = 2010-08-01 | pmid = 20698820 | doi = 10.2174/138161210793176572 }}</ref> and eventually cause neuronal death<ref>{{cite journal | vauthors = Wang WY, Tan MS, Yu JT, Tan L | title = Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease | journal = Annals of Translational Medicine | volume = 3 | issue = 10 | pages = 136 | date = June 2015 | pmid = 26207229 | pmc = 4486922 | doi = 10.3978/j.issn.2305-5839.2015.03.49 }}</ref>. The loss of synaptic functioning and later neuronal death is responsible for the cognitive impairments and loss of volume in key brain regions which are associated with AD<ref>{{cite journal | vauthors = Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T | display-authors = 6 | title = Inflammation and Alzheimer's disease | journal = Neurobiology of Aging | volume = 21 | issue = 3 | pages = 383–421 | date = 2000 | pmid = 10858586 | pmc = 3887148 | doi = 10.1016/s0197-4580(00)00124-x }}</ref>. IL-1B, IL-6, and TNF-a cause further production of Aβ oligomers, as well as tau hyperphosphorylation, leading to continued microglia activation and creating a feed forward mechanism in which Aβ production is increased and Aβ clearance is decreased eventually causing the formation of Aβ plaques<ref>{{cite journal | vauthors = Tuppo EE, Arias HR | title = The role of inflammation in Alzheimer's disease | journal = The International Journal of Biochemistry & Cell Biology | volume = 37 | issue = 2 | pages = 289–305 | date = February 2005 | pmid = 15474976 | doi = 10.1016/j.biocel.2004.07.009 }}</ref><ref>{{cite journal | vauthors = Meraz-Ríos MA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernández J, Campos-Peña V | title = Inflammatory process in Alzheimer's Disease | journal = Frontiers in Integrative Neuroscience | volume = 7 | pages = 59 | date = 2013 | pmid = 23964211 | pmc = 3741576 | doi = 10.3389/fnint.2013.00059 }}</ref>.
 ===Isoprenoid changes===
-A 1994 study <ref>{{cite journal|pmid=7950967|year=1994|last1=Edlund|first1=C|last2=Söderberg|first2=M|last3=Kristensson|first3=K|title=Isoprenoids in aging and neurodegeneration|volume=25|issue=1|pages=35–8|journal=Neurochemistry International|doi=10.1016/0197-0186(94)90050-7}}</ref> showed that the [[isoprenoid]] changes in Alzheimer's disease differ from those occurring during normal aging and that this disease cannot, therefore, be regarded as a result of [[premature aging]]. During aging the [[human brain]] shows a progressive increase in levels of [[dolichol]], a reduction in levels of [[ubiquinone]], but relatively unchanged concentrations of [[cholesterol]] and dolichyl phosphate. In Alzheimer's disease, the situation is reversed with decreased levels of [[dolichol]] and increased levels of [[ubiquinone]]. The concentrations of dolichyl phosphate are also increased, while [[cholesterol]] remains unchanged. The increase in the sugar carrier dolichyl phosphate may reflect an increased rate of [[glycosylation]] in the diseased brain and the increase in the endogenous [[anti-oxidant]] [[ubiquinone]] an attempt to protect the brain from [[oxidative stress]], for instance induced by [[lipid peroxidation]].<ref>{{cite journal|vauthors=Edlund C, Söderberg M, Kristensson K |journal=Neurochem Int|date=July 1994|volume=25|issue=1|pages=35–8|doi=10.1016/0197-0186(94)90050-7|pmid=7950967|title=Isoprenoids in aging and neurodegeneration}}</ref> [[solagran#Ropren|Ropren]], identified previously in Russia, is neuroprotective in a rat model of Alzheimer's disease.<ref>{{cite journal|pmid=16913416|language=ru|lay-url=http://www.biotechnologynews.net/storyview.asp?storyid=68509&sectionsource=s0/|year=2006|last1=Sviderskii|first1=VL|last2=Khovanskikh|first2=AE|last3=Rozengart|first3=EV|last4=Moralev|first4=SN|last5=Yagodina|first5=OV|last6=Gorelkin|first6=VS|last7=Basova|first7=IN|last8=Kormilitsyn|first8=BN|last9=Nikitina|first9=TV|last10=Roshchin|first10=V. I.|last11=Sultanov|first11=V. S.|title=A comparative study of the effect of the polyprenol preparation ropren from coniferous plants on the key enzymes of the cholinergic and monoaminergic types of nervous transmission|volume=408|pages=148–51|journal=Doklady Biochemistry and Biophysics|doi=10.1134/S1607672906030112}}</ref><ref>{{cite journal|last1=Fedotova|first1=J|last2=Soultanov|first2=V|last3=Nikitina|first3=T|last4=Roschin|first4=V|last5=Ordayn|first5=N|title=Ropren(®) is a polyprenol preparation from coniferous plants that ameliorates cognitive deficiency in a rat model of beta-amyloid peptide-(25-35)-induced amnesia.|journal=Phytomedicine|date=15 March 2012|volume=19|issue=5|pages=451–6|doi=10.1016/j.phymed.2011.09.073|pmid=22305275}}</ref>
+A 1994 study <ref>{{cite journal | vauthors = Edlund C, Söderberg M, Kristensson K | title = Isoprenoids in aging and neurodegeneration | journal = Neurochemistry International | volume = 25 | issue = 1 | pages = 35–8 | date = July 1994 | pmid = 7950967 | doi = 10.1016/0197-0186(94)90050-7 }}</ref> showed that the [[isoprenoid]] changes in Alzheimer's disease differ from those occurring during normal aging and that this disease cannot, therefore, be regarded as a result of [[premature aging]]. During aging the [[human brain]] shows a progressive increase in levels of [[dolichol]], a reduction in levels of [[ubiquinone]], but relatively unchanged concentrations of [[cholesterol]] and dolichyl phosphate. In Alzheimer's disease, the situation is reversed with decreased levels of [[dolichol]] and increased levels of [[ubiquinone]]. The concentrations of dolichyl phosphate are also increased, while [[cholesterol]] remains unchanged. The increase in the sugar carrier dolichyl phosphate may reflect an increased rate of [[glycosylation]] in the diseased brain and the increase in the endogenous [[anti-oxidant]] [[ubiquinone]] an attempt to protect the brain from [[oxidative stress]], for instance induced by [[lipid peroxidation]].<ref>{{cite journal | vauthors = Edlund C, Söderberg M, Kristensson K | title = Isoprenoids in aging and neurodegeneration | journal = Neurochemistry International | volume = 25 | issue = 1 | pages = 35–8 | date = July 1994 | pmid = 7950967 | doi = 10.1016/0197-0186(94)90050-7 }}</ref> [[solagran#Ropren|Ropren]], identified previously in Russia, is neuroprotective in a rat model of Alzheimer's disease.<ref>{{cite journal | vauthors = Sviderskii VL, Khovanskikh AE, Rozengart EV, Moralev SN, Yagodina OV, Gorelkin VS, Basova IN, Kormilitsyn BN, Nikitina TV, Roshchin VI, Sultanov VS | display-authors = 6 | title = A comparative study of the effect of the polyprenol preparation ropren from coniferous plants on the key enzymes of the cholinergic and monoaminergic types of nervous transmission | language = ru | journal = Doklady. Biochemistry and Biophysics | volume = 408 | pages = 148–51 | year = 2006 | pmid = 16913416 | doi = 10.1134/S1607672906030112 | lay-url = http://www.biotechnologynews.net/storyview.asp?storyid=68509&sectionsource=s0/ }}</ref><ref>{{cite journal | vauthors = Fedotova J, Soultanov V, Nikitina T, Roschin V, Ordayn N | title = Ropren(®) is a polyprenol preparation from coniferous plants that ameliorates cognitive deficiency in a rat model of beta-amyloid peptide-(25-35)-induced amnesia | journal = Phytomedicine | volume = 19 | issue = 5 | pages = 451–6 | date = March 2012 | pmid = 22305275 | doi = 10.1016/j.phymed.2011.09.073 }}</ref>
 ==Glucose consumption==
-The human brain is one of the most metabolically active organs in the body and metabolizes a large amount of glucose to produce cellular energy in the form of [[adenosine triphosphate]] (ATP).<ref name=Reference2>{{cite journal |vauthors=Cunnane S, Nugent S, Roy M | year = 2011 | title = Brain fuel metabolism, aging, and Alzheimer's disease | journal = Nutrition | volume = 27 | issue = 1| pages = 3–20 | doi=10.1016/j.nut.2010.07.021|display-authors=etal | pmid=21035308 | pmc=3478067}}</ref> Despite its high energy demands, the brain is relatively inflexible in its ability to utilize substrates for energy production and relies almost entirely on circulating glucose for its energy needs.<ref name=Reference7>{{cite journal |vauthors=Costantini LC, Barr LJ, Vogel JL, Henderson ST | year = 2008 | title = Hypometabolism as a therapeutic target in Alzheimer's disease | journal = BMC Neurosci | volume = 9 | issue = Suppl 2| page = S16 | doi=10.1186/1471-2202-9-s2-s16| pmid = 19090989 | pmc = 2604900 }}</ref> This dependence on glucose puts the brain at risk if the supply of glucose is interrupted, or if its ability to metabolize glucose becomes defective. If the brain is not able to produce ATP, synapses cannot be maintained and cells cannot function, ultimately leading to impaired cognition.<ref name="Reference7"/>
+The human brain is one of the most metabolically active organs in the body and metabolizes a large amount of glucose to produce cellular energy in the form of [[adenosine triphosphate]] (ATP).<ref name=Reference2>{{cite journal | vauthors = Cunnane S, Nugent S, Roy M, Courchesne-Loyer A, Croteau E, Tremblay S, Castellano A, Pifferi F, Bocti C, Paquet N, Begdouri H, Bentourkia M, Turcotte E, Allard M, Barberger-Gateau P, Fulop T, Rapoport SI | display-authors = 6 | title = Brain fuel metabolism, aging, and Alzheimer's disease | journal = Nutrition | volume = 27 | issue = 1 | pages = 3–20 | date = January 2011 | pmid = 21035308 | pmc = 3478067 | doi = 10.1016/j.nut.2010.07.021 }}</ref> Despite its high energy demands, the brain is relatively inflexible in its ability to utilize substrates for energy production and relies almost entirely on circulating glucose for its energy needs.<ref name=Reference7>{{cite journal | vauthors = Costantini LC, Barr LJ, Vogel JL, Henderson ST | title = Hypometabolism as a therapeutic target in Alzheimer's disease | journal = BMC Neuroscience | volume = 9 Suppl 2 | issue = Suppl 2 | pages = S16 | date = December 2008 | pmid = 19090989 | pmc = 2604900 | doi = 10.1186/1471-2202-9-s2-s16 }}</ref> This dependence on glucose puts the brain at risk if the supply of glucose is interrupted, or if its ability to metabolize glucose becomes defective. If the brain is not able to produce ATP, synapses cannot be maintained and cells cannot function, ultimately leading to impaired cognition.<ref name="Reference7"/>
-Imaging studies have shown decreased utilization of glucose in the brains of Alzheimer’s disease patients early in the disease, before clinical signs of cognitive impairment occur. This decrease in [[glucose metabolism]] worsens as clinical symptoms develop and the disease progresses.<ref name=Reference8>{{cite journal | author = Hoyer S | year = 1992 | title = Oxidative energy metabolism in Alzheimer brain. Studies in early-onset and late-onset cases | journal = Mol Chem Neuropathol | volume = 16 | issue = 3| pages = 207–224 | doi=10.1007/bf03159971 | pmid=1418218}}</ref><ref name=Reference9>{{cite journal |vauthors=Small GW, Ercoli LM, Silverman DH | year = 2000 | title = Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease | doi = 10.1073/pnas.090106797 | pmid = 10811879 | journal = Proc Natl Acad Sci U S A | volume = 97 | issue = 11| pages = 6037–6042 |display-authors=etal|bibcode = 2000PNAS...97.6037S |pmc = 18554 }}</ref>  Studies have found a 17%-24% decline in cerebral glucose metabolism in patients with Alzheimer’s disease, compared with age-matched controls.<ref name=Reference10>{{cite journal |vauthors=De Leon MJ, Ferris SH, George AE | year = 1983 | title = Positron emission tomographic studies of aging and Alzheimer disease | journal = Am J Neuroradiol | volume = 4 | issue = 3| pages = 568–571 |display-authors=etal}}</ref> Numerous imaging studies have since confirmed this observation.
+Imaging studies have shown decreased utilization of glucose in the brains of Alzheimer’s disease patients early in the disease, before clinical signs of cognitive impairment occur. This decrease in [[glucose metabolism]] worsens as clinical symptoms develop and the disease progresses.<ref name=Reference8>{{cite journal | vauthors = Hoyer S | title = Oxidative energy metabolism in Alzheimer brain. Studies in early-onset and late-onset cases | journal = Molecular and Chemical Neuropathology | volume = 16 | issue = 3 | pages = 207–24 | date = June 1992 | pmid = 1418218 | doi = 10.1007/bf03159971 }}</ref><ref name=Reference9>{{cite journal | vauthors = Small GW, Ercoli LM, Silverman DH, Huang SC, Komo S, Bookheimer SY, Lavretsky H, Miller K, Siddarth P, Rasgon NL, Mazziotta JC, Saxena S, Wu HM, Mega MS, Cummings JL, Saunders AM, Pericak-Vance MA, Roses AD, Barrio JR, Phelps ME | display-authors = 6 | title = Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 11 | pages = 6037–42 | date = May 2000 | pmid = 10811879 | pmc = 18554 | doi = 10.1073/pnas.090106797 | bibcode = 2000PNAS...97.6037S }}</ref>  Studies have found a 17%-24% decline in cerebral glucose metabolism in patients with Alzheimer’s disease, compared with age-matched controls.<ref name=Reference10>{{cite journal |vauthors=De Leon MJ, Ferris SH, George AE | year = 1983 | title = Positron emission tomographic studies of aging and Alzheimer disease | journal = Am J Neuroradiol | volume = 4 | issue = 3| pages = 568–571 |display-authors=etal}}</ref> Numerous imaging studies have since confirmed this observation.
-Abnormally low rates of cerebral glucose metabolism are found in a characteristic pattern in the Alzheimer’s disease brain, particularly in the posterior cingulate, parietal, temporal, and prefrontal cortices. These brain regions are believed to control multiple aspects of [[memory]] and [[cognition]]. This metabolic pattern is reproducible and has even been proposed as a diagnostic tool for Alzheimer’s disease. Moreover, diminished cerebral glucose metabolism (DCGM) correlates with plaque density and cognitive deficits in patients with more advanced disease.<ref name="Reference10"/><ref name=Reference11>{{cite journal |vauthors=Meier-Ruge W, Bertoni-Freddari C, Iwangoff P | year = 1994 | title = Changes in brain glucose metabolism as a key to the pathogenesis of Alzheimer's disease | journal = Gerontology | volume = 40 | issue = 5| pages = 246–252 | doi=10.1159/000213592 | pmid=7959080}}</ref>
+Abnormally low rates of cerebral glucose metabolism are found in a characteristic pattern in the Alzheimer’s disease brain, particularly in the posterior cingulate, parietal, temporal, and prefrontal cortices. These brain regions are believed to control multiple aspects of [[memory]] and [[cognition]]. This metabolic pattern is reproducible and has even been proposed as a diagnostic tool for Alzheimer’s disease. Moreover, diminished cerebral glucose metabolism (DCGM) correlates with plaque density and cognitive deficits in patients with more advanced disease.<ref name="Reference10"/><ref name=Reference11>{{cite journal | vauthors = Meier-Ruge W, Bertoni-Freddari C, Iwangoff P | title = Changes in brain glucose metabolism as a key to the pathogenesis of Alzheimer's disease | journal = Gerontology | volume = 40 | issue = 5 | pages = 246–52 | year = 1994 | pmid = 7959080 | doi = 10.1159/000213592 }}</ref>
-Diminished cerebral glucose metabolism (DCGM) may not be solely an artifact of brain cell loss since it occurs in asymptomatic patients at risk for Alzheimer’s disease, such as patients homozygous for the epsilon 4 variant of the [[apolipoprotein E]] gene (APOE4, a genetic risk factor for Alzheimer’s disease), as well as in inherited forms of Alzheimer’s disease.<ref name=Reference4>{{cite journal |vauthors=Reiman EM, Chen K, Alexander GE | year = 2004 | title = Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia | doi = 10.1073/pnas.2635903100 | pmid = 14688411 | journal = Proc Natl Acad Sci USA | volume = 101 | issue = 1| pages = 284–289 |display-authors=etal|bibcode = 2003PNAS..101..284R |pmc = 314177 }}</ref> Given that DCGM occurs before other clinical and pathological changes occur, it is unlikely to be due to the gross cell loss observed in Alzheimer’s disease.<ref name="Reference7"/>
+Diminished cerebral glucose metabolism (DCGM) may not be solely an artifact of brain cell loss since it occurs in asymptomatic patients at risk for Alzheimer’s disease, such as patients homozygous for the epsilon 4 variant of the [[apolipoprotein E]] gene (APOE4, a genetic risk factor for Alzheimer’s disease), as well as in inherited forms of Alzheimer’s disease.<ref name=Reference4>{{cite journal | vauthors = Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D, Saunders AM, Hardy J | display-authors = 6 | title = Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 1 | pages = 284–9 | date = January 2004 | pmid = 14688411 | pmc = 314177 | doi = 10.1073/pnas.2635903100 | bibcode = 2003PNAS..101..284R }}</ref> Given that DCGM occurs before other clinical and pathological changes occur, it is unlikely to be due to the gross cell loss observed in Alzheimer’s disease.<ref name="Reference7"/>
-In imaging studies involving young adult APOE4 carriers, where there were no signs of cognitive impairment, diminished cerebral glucose metabolism (DCGM) was detected in the same areas of the brain as older subjects with Alzheimer’s disease.<ref name=Reference4 /> However, DCGM is not exclusive to APOE4 carriers. By the time Alzheimer’s has been diagnosed, DCGM occurs in genotypes APOE3/E4, APOE3/E3, and APOE4/E4.<ref name=Reference12>{{cite journal |vauthors=Corder EH, Jelic V, Basun H | year = 1997 | title = No difference in cerebral glucose metabolism in patients with Alzheimer disease and differing apolipoprotein E genotypes | journal = Arch Neurol | volume = 54 | issue = 3| pages = 273–277 | doi=10.1001/archneur.1997.00550150035013|display-authors=etal}}</ref> Thus, DCGM is a metabolic [[biomarker]] for the disease state.<ref>{{cite news|title=Diminished cerebral glucose metabolism: A key pathology in Alzheimer's disease|url=http://www.about-axona.com/assets/files/us-en/hcp/pdf/KAXO1056_DCGM_Adv_NR_MV01a.pdf|access-date=9 October 2013}}</ref>
+In imaging studies involving young adult APOE4 carriers, where there were no signs of cognitive impairment, diminished cerebral glucose metabolism (DCGM) was detected in the same areas of the brain as older subjects with Alzheimer’s disease.<ref name=Reference4 /> However, DCGM is not exclusive to APOE4 carriers. By the time Alzheimer’s has been diagnosed, DCGM occurs in genotypes APOE3/E4, APOE3/E3, and APOE4/E4.<ref name=Reference12>{{cite journal | vauthors = Corder EH, Jelic V, Basun H, Lannfelt L, Valind S, Winblad B, Nordberg A | title = No difference in cerebral glucose metabolism in patients with Alzheimer disease and differing apolipoprotein E genotypes | journal = Archives of Neurology | volume = 54 | issue = 3 | pages = 273–7 | date = March 1997 | pmid = 9074396 | doi = 10.1001/archneur.1997.00550150035013 }}</ref> Thus, DCGM is a metabolic [[biomarker]] for the disease state.<ref>{{cite news|title=Diminished cerebral glucose metabolism: A key pathology in Alzheimer's disease|url=http://www.about-axona.com/assets/files/us-en/hcp/pdf/KAXO1056_DCGM_Adv_NR_MV01a.pdf|access-date=9 October 2013}}</ref>
 == Insulin signaling ==
-A connection has been established between Alzheimer's disease and diabetes during the past decade, as [[insulin resistance]], which is a characteristic hallmark of [[Diabetes mellitus|diabetes]], has also been observed in brains of subjects suffering from Alzheimer's disease.<ref name=":0">{{Cite journal|last=Felice|first=Fernanda G. De|date=2013-02-01|title=Alzheimer's disease and insulin resistance: translating basic science into clinical applications|journal=The Journal of Clinical Investigation|language=en|volume=123|issue=2|doi=10.1172/JCI64595|issn=0021-9738|pmc=3561831|pmid=23485579|pages=531–539}}</ref> Neurotoxic oligomeric [[Amyloid beta|amyloid-β]] species decrease the expression of insulin receptors on the neuronal cell surface<ref>{{Cite journal|last=Felice|first=Fernanda G. De|last2=Vieira|first2=Marcelo N. N.|last3=Bomfim|first3=Theresa R.|last4=Decker|first4=Helena|last5=Velasco|first5=Pauline T.|last6=Lambert|first6=Mary P.|last7=Viola|first7=Kirsten L.|last8=Zhao|first8=Wei-Qin|last9=Ferreira|first9=Sergio T.|date=2009-02-02|title=Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers|journal=Proceedings of the National Academy of Sciences|language=en|pages=1971–6|doi=10.1073/pnas.0809158106|issn=0027-8424|pmc=2634809|pmid=19188609|volume=106|issue=6|bibcode=2009PNAS..106.1971D}}</ref> and abolish neuronal insulin signaling.<ref name=":0" /> It has been suggested that neuronal [[ganglioside]]s, which take part in the formation of membrane [[lipid microdomain]]s, facilitate amyloid-β-induced removal of the insulin receptors from the neuronal surface.<ref>{{Cite journal|last=Herzer|first=Silke|last2=Meldner|first2=Sascha|last3=Rehder|first3=Klara|last4=Gröne|first4=Hermann-Josef|last5=Nordström|first5=Viola|date=2016-01-01|title=Lipid microdomain modification sustains neuronal viability in models of Alzheimer's disease|journal=Acta Neuropathologica Communications|volume=4|issue=1|pages=103|doi=10.1186/s40478-016-0354-z|issn=2051-5960|pmc=5027102|pmid=27639375}}</ref> In Alzheimer's disease, oligomeric amyloid-β species trigger [[Tumor necrosis factor alpha|TNF-α]] signaling.<ref name=":0" /> c-Jun N-terminal kinase activation by TNF-α in turn activates stress-related kinases and results in IRS-1 serine phosphorylation, which subsequently blocks downstream insulin signaling.<ref name=":0" /><ref>{{Cite journal|last=Wan|first=Q.|last2=Xiong|first2=Z. G.|last3=Man|first3=H. Y.|last4=Ackerley|first4=C. A.|last5=Braunton|first5=J.|last6=Lu|first6=W. Y.|last7=Becker|first7=L. E.|last8=MacDonald|first8=J. F.|last9=Wang|first9=Y. T.|date=1997-08-14|title=Recruitment of functional GABAA receptors to postsynaptic domains by insulin|journal=Nature|language=en|volume=388|issue=6643|pages=686–690|doi=10.1038/41792|pmid=9262404|issn=0028-0836}}</ref><ref>{{Cite journal|last=Saraiva|first=Leonardo M.|last2=Seixas da Silva|first2=Gisele S.|last3=Galina|first3=Antonio|last4=da-Silva|first4=Wagner S.|last5=Klein|first5=William L.|last6=Ferreira|first6=Sérgio T.|last7=De Felice|first7=Fernanda G.|date=2010-01-01|title=Amyloid-β triggers the release of neuronal hexokinase 1 from mitochondria|journal=PLOS ONE|volume=5|issue=12|pages=e15230|doi=10.1371/journal.pone.0015230|issn=1932-6203|pmc=3002973|pmid=21179577|bibcode=2010PLoSO...515230S}}</ref> The resulting insulin resistance contributes to cognitive impairment. Consequently, increasing  neuronal insulin sensitivity and signaling may constitute a novel therapeutic approach to treat Alzheimer's disease.<ref>{{Cite journal|last=Craft|first=Suzanne|date=2012-07-01|title=Alzheimer disease: Insulin resistance and AD—extending the translational path|journal=Nature Reviews Neurology|language=en|volume=8|issue=7|pages=360–362|doi=10.1038/nrneurol.2012.112|pmid=22710630|issn=1759-4758|url=https://zenodo.org/record/1233572/files/article.pdf}}</ref><ref>{{Cite journal|last=de la Monte|first=Suzanne M.|date=2012-01-01|title=Brain insulin resistance and deficiency as therapeutic targets in Alzheimer's disease|journal=Current Alzheimer Research|volume=9|issue=1|pages=35–66|issn=1875-5828|pmc=3349985|pmid=22329651|doi=10.2174/156720512799015037}}</ref>
+A connection has been established between Alzheimer's disease and diabetes during the past decade, as [[insulin resistance]], which is a characteristic hallmark of [[Diabetes mellitus|diabetes]], has also been observed in brains of subjects suffering from Alzheimer's disease.<ref name=":0">{{cite journal | vauthors = De Felice FG | title = Alzheimer's disease and insulin resistance: translating basic science into clinical applications | journal = The Journal of Clinical Investigation | volume = 123 | issue = 2 | pages = 531–9 | date = February 2013 | pmid = 23485579 | pmc = 3561831 | doi = 10.1172/JCI64595 }}</ref> Neurotoxic oligomeric [[Amyloid beta|amyloid-β]] species decrease the expression of insulin receptors on the neuronal cell surface<ref>{{cite journal | vauthors = De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, Viola KL, Zhao WQ, Ferreira ST, Klein WL | display-authors = 6 | title = Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 6 | pages = 1971–6 | date = February 2009 | pmid = 19188609 | pmc = 2634809 | doi = 10.1073/pnas.0809158106 | bibcode = 2009PNAS..106.1971D }}</ref> and abolish neuronal insulin signaling.<ref name=":0" /> It has been suggested that neuronal [[ganglioside]]s, which take part in the formation of membrane [[lipid microdomain]]s, facilitate amyloid-β-induced removal of the insulin receptors from the neuronal surface.<ref>{{cite journal | vauthors = Herzer S, Meldner S, Rehder K, Gröne HJ, Nordström V | title = Lipid microdomain modification sustains neuronal viability in models of Alzheimer's disease | journal = Acta Neuropathologica Communications | volume = 4 | issue = 1 | pages = 103 | date = September 2016 | pmid = 27639375 | pmc = 5027102 | doi = 10.1186/s40478-016-0354-z }}</ref> In Alzheimer's disease, oligomeric amyloid-β species trigger [[Tumor necrosis factor alpha|TNF-α]] signaling.<ref name=":0" /> c-Jun N-terminal kinase activation by TNF-α in turn activates stress-related kinases and results in IRS-1 serine phosphorylation, which subsequently blocks downstream insulin signaling.<ref name=":0" /><ref>{{cite journal | vauthors = Wan Q, Xiong ZG, Man HY, Ackerley CA, Braunton J, Lu WY, Becker LE, MacDonald JF, Wang YT | display-authors = 6 | title = Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin | journal = Nature | volume = 388 | issue = 6643 | pages = 686–90 | date = August 1997 | pmid = 9262404 | doi = 10.1038/41792 }}</ref><ref>{{cite journal | vauthors = Saraiva LM, Seixas da Silva GS, Galina A, da-Silva WS, Klein WL, Ferreira ST, De Felice FG | title = Amyloid-β triggers the release of neuronal hexokinase 1 from mitochondria | journal = PloS One | volume = 5 | issue = 12 | pages = e15230 | date = December 2010 | pmid = 21179577 | pmc = 3002973 | doi = 10.1371/journal.pone.0015230 | bibcode = 2010PLoSO...515230S }}</ref> The resulting insulin resistance contributes to cognitive impairment. Consequently, increasing  neuronal insulin sensitivity and signaling may constitute a novel therapeutic approach to treat Alzheimer's disease.<ref>{{cite journal | vauthors = Craft S | title = Alzheimer disease: Insulin resistance and AD--extending the translational path | journal = Nature Reviews. Neurology | volume = 8 | issue = 7 | pages = 360–2 | date = June 2012 | pmid = 22710630 | doi = 10.1038/nrneurol.2012.112 }}</ref><ref>{{cite journal | vauthors = de la Monte SM | title = Brain insulin resistance and deficiency as therapeutic targets in Alzheimer's disease | journal = Current Alzheimer Research | volume = 9 | issue = 1 | pages = 35–66 | date = January 2012 | pmid = 22329651 | pmc = 3349985 | doi = 10.2174/156720512799015037 }}</ref>
 ==Oxidative stress==
-[[Oxidative stress]] is emerging as a key factor in the [[pathogenesis]] of AD.<ref name="pmid28785371">{{cite journal |vauthors=Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L |title=Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications |journal=Oxid Med Cell Longev |volume=2017 |pages=1–11 |date=2017 |pmid=28785371 |pmc=5529664 |doi=10.1155/2017/2525967 }}</ref>  [[Reactive oxygen species]] (ROS) over-production is thought to play a critical role in the accumulation and deposition of [[amyloid beta]] in AD.<ref name="pmid24733654">{{cite journal |vauthors=Bonda DJ, Wang X, Lee HG, Smith MA, Perry G, Zhu X |title=Neuronal failure in Alzheimer's disease: a view through the oxidative stress looking-glass |journal=Neurosci Bull |volume=30 |issue=2 |pages=243–52 |date=April 2014 |pmid=24733654 |pmc=4097013 |doi=10.1007/s12264-013-1424-x }}</ref>  Brains of AD patients have elevated levels of [[DNA oxidation|oxidative DNA damage]] in both [[nuclear DNA|nuclear]] and [[mitochondrial DNA]], but the mitochondrial DNA has approximately 10-fold higher levels than nuclear DNA.<ref name="pmid15857398">{{cite journal |vauthors=Wang J, Xiong S, Xie C, Markesbery WR, Lovell MA |title=Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer's disease |journal=J. Neurochem. |volume=93 |issue=4 |pages=953–62 |date=May 2005 |pmid=15857398 |doi=10.1111/j.1471-4159.2005.03053.x |doi-access=free }}</ref>  Aged mitochondria may be the critical factor in the origin of [[neurodegeneration]] in AD.<ref name="pmid24733654" />  Even individuals with [[mild cognitive impairment]], the phase between normal aging and early dementia, have increased oxidative damage in their nuclear and mitochondrial brain DNA<ref name="pmid16405502">{{cite journal |vauthors=Wang J, Markesbery WR, Lovell MA |title=Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment |journal=J. Neurochem. |volume=96 |issue=3 |pages=825–32 |date=February 2006 |pmid=16405502 |doi=10.1111/j.1471-4159.2005.03615.x |doi-access=free }}</ref> (see [[Aging brain]]).
+[[Oxidative stress]] is emerging as a key factor in the [[pathogenesis]] of AD.<ref name="pmid28785371">{{cite journal | vauthors = Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L | title = Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications | journal = Oxidative Medicine and Cellular Longevity | volume = 2017 | pages = 2525967 | date = 2017 | pmid = 28785371 | pmc = 5529664 | doi = 10.1155/2017/2525967 }}</ref>  [[Reactive oxygen species]] (ROS) over-production is thought to play a critical role in the accumulation and deposition of [[amyloid beta]] in AD.<ref name="pmid24733654">{{cite journal | vauthors = Bonda DJ, Wang X, Lee HG, Smith MA, Perry G, Zhu X | title = Neuronal failure in Alzheimer's disease: a view through the oxidative stress looking-glass | journal = Neuroscience Bulletin | volume = 30 | issue = 2 | pages = 243–52 | date = April 2014 | pmid = 24733654 | pmc = 4097013 | doi = 10.1007/s12264-013-1424-x }}</ref>  Brains of AD patients have elevated levels of [[DNA oxidation|oxidative DNA damage]] in both [[nuclear DNA|nuclear]] and [[mitochondrial DNA]], but the mitochondrial DNA has approximately 10-fold higher levels than nuclear DNA.<ref name="pmid15857398">{{cite journal | vauthors = Wang J, Xiong S, Xie C, Markesbery WR, Lovell MA | title = Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer's disease | journal = Journal of Neurochemistry | volume = 93 | issue = 4 | pages = 953–62 | date = May 2005 | pmid = 15857398 | doi = 10.1111/j.1471-4159.2005.03053.x | doi-access = free }}</ref>  Aged mitochondria may be the critical factor in the origin of [[neurodegeneration]] in AD.<ref name="pmid24733654" />  Even individuals with [[mild cognitive impairment]], the phase between normal aging and early dementia, have increased oxidative damage in their nuclear and mitochondrial brain DNA<ref name="pmid16405502">{{cite journal | vauthors = Wang J, Markesbery WR, Lovell MA | title = Increased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment | journal = Journal of Neurochemistry | volume = 96 | issue = 3 | pages = 825–32 | date = February 2006 | pmid = 16405502 | doi = 10.1111/j.1471-4159.2005.03615.x | doi-access = free }}</ref> (see [[Aging brain]]).
 ==Large gene instability hypothesis==
-A bioinformatics analysis in 2017<ref name="B1897">{{cite journal |year=2017 |title= Alzheimer's disease: the large gene instability hypothesis |journal= bioRxiv |doi= 10.1101/189712|last1= Soheili-Nezhad |first1= Sourena |doi-access= free }}</ref> revealed that extremely large human genes are significantly over-expressed in brain and take part in the postsynaptic architecture. These genes are also highly enriched in cell adhesion Gene Ontology (GO) terms and often map to chromosomal fragile sites.<ref>{{Cite journal|last=Smith|first=D.I.|date=2005-10-14|title=Common fragile sites, extremely large genes, neural development and cancer|url=http://www.cancerletters.info/article/S0304-3835(05)00823-2/fulltext|journal=Cancer Letters|language=en|volume=232|issue=1|pages=48–57|doi=10.1016/j.canlet.2005.06.049|pmid=16221525|issn=0304-3835}}</ref> The majority of known Alzheimer's disease risk gene products including the amyloid precursor protein (APP) and gamma-secretase, as well as the APOE receptors and GWAS risk loci take part in similar cell adhesion mechanisms. It was concluded that dysfunction of cell and synaptic adhesion is central to Alzheimer's disease pathogenesis, and mutational instability of large synaptic adhesion genes may be the etiological trigger of neurotransmission disruption and synaptic loss in brain aging. As a typical example, this hypothesis explains the APOE risk locus of AD in context of signaling of its giant lipoprotein receptor, LRP1b which is a large tumor-suppressor gene with brain-specific expression and also maps to an unstable chromosomal fragile site. The large gene instability hypothesis puts the DNA damage mechanism at the center of Alzheimer's disease pathophysiology.
+A bioinformatics analysis in 2017<ref name="B1897">{{cite journal | vauthors = Soheili-Nezhad S |year=2017 |title= Alzheimer's disease: the large gene instability hypothesis |journal= bioRxiv |doi= 10.1101/189712 |doi-access= free }}</ref> revealed that extremely large human genes are significantly over-expressed in brain and take part in the postsynaptic architecture. These genes are also highly enriched in cell adhesion Gene Ontology (GO) terms and often map to chromosomal fragile sites.<ref>{{cite journal | vauthors = Smith DI, Zhu Y, McAvoy S, Kuhn R | title = Common fragile sites, extremely large genes, neural development and cancer | journal = Cancer Letters | volume = 232 | issue = 1 | pages = 48–57 | date = January 2006 | pmid = 16221525 | doi = 10.1016/j.canlet.2005.06.049 }}</ref> The majority of known Alzheimer's disease risk gene products including the amyloid precursor protein (APP) and gamma-secretase, as well as the APOE receptors and GWAS risk loci take part in similar cell adhesion mechanisms. It was concluded that dysfunction of cell and synaptic adhesion is central to Alzheimer's disease pathogenesis, and mutational instability of large synaptic adhesion genes may be the etiological trigger of neurotransmission disruption and synaptic loss in brain aging. As a typical example, this hypothesis explains the APOE risk locus of AD in context of signaling of its giant lipoprotein receptor, LRP1b which is a large tumor-suppressor gene with brain-specific expression and also maps to an unstable chromosomal fragile site. The large gene instability hypothesis puts the DNA damage mechanism at the center of Alzheimer's disease pathophysiology.
 ==DNA damage==
-Naturally occurring [[DNA damage (naturally occurring)|DNA double-strand breaks]] (DSBs) arise in human cells largely from single-strand breaks induced by various processes including the activity of reactive oxygen species, topoisomerases, and hydrolysis due to thermal fluctuations.<ref>Vilenchik MM, Knudson AG. Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12871-6. doi: 10.1073/pnas.2135498100. Epub 2003 Oct 17. {{PMID|14566050}}; PMCID: PMC240711</ref>  In neurons DSBs are induced by a type II topoisomerase as part of the physiologic process of memory formation.<ref>Madabhushi R, Gao F, Pfenning AR, Pan L, Yamakawa S, Seo J, Rueda R, Phan TX, Yamakawa H, Pao PC, Stott RT, Gjoneska E, Nott A, Cho S, Kellis M, Tsai LH. Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes. Cell. 2015 Jun 18;161(7):1592-605. doi: 10.1016/j.cell.2015.05.032. Epub 2015 Jun 4. {{PMID|26052046}}; PMCID: PMC4886855</ref>  DSBs are present in both neurons and astrocytes in the postmortem human [[hippocampus]] of AD patients at a higher level than in non-AD individuals.<ref name = Thadathil2021>Thadathil N, Delotterie DF, Xiao J, Hori R, McDonald MP, Khan MM. DNA Double-Strand Break Accumulation in Alzheimer's Disease: Evidence from Experimental Models and Postmortem Human Brains. Mol Neurobiol. 2021 Jan;58(1):118-131. doi: 10.1007/s12035-020-02109-8. Epub 2020 Sep 8. {{PMID|32895786}}</ref>   AD is associated with an accumulation of DSBs in neurons and astrocytes in the hippocampus and frontal cortex from early stages onward.<ref>Shanbhag NM, Evans MD, Mao W, Nana AL, Seeley WW, Adame A, Rissman RA, Masliah E, Mucke L. Early neuronal accumulation of DNA double strand breaks in Alzheimer's disease. Acta Neuropathol Commun. 2019 May 17;7(1):77. doi: 10.1186/s40478-019-0723-5. {{PMID|31101070}}; PMCID: PMC6524256</ref> DSBs are increased in the vicinity of amyloid plaques in the hippocampus, indicating a potential role for Aβ in DSB accumulation or vice versa.<ref name = Thadathil2021/>  The predominant mechanism for repairing DNA double-strand breaks is non-homologous end joining (NHEJ), a mechanism that utilizes the DNA-dependent protein kinase (DNA-PK) complex.  The end joining activity and protein levels of DNA-PK catalytic subunit are significantly lower in AD brains than in normal brains.<ref>Shackelford DA. DNA end joining activity is reduced in Alzheimer's disease. Neurobiol Aging. 2006 Apr;27(4):596-605. doi: 10.1016/j.neurobiolaging.2005.03.009. {{PMID|15908050}}</ref>
+Naturally occurring [[DNA damage (naturally occurring)|DNA double-strand breaks]] (DSBs) arise in human cells largely from single-strand breaks induced by various processes including the activity of reactive oxygen species, topoisomerases, and hydrolysis due to thermal fluctuations.<ref name="pmid14566050">{{cite journal | vauthors = Vilenchik MM, Knudson AG | title = Endogenous DNA double-strand breaks: production, fidelity of repair, and induction of cancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 22 | pages = 12871–6 | date = October 2003 | pmid = 14566050 | pmc = 240711 | doi = 10.1073/pnas.2135498100 }}</ref>  In neurons DSBs are induced by a type II topoisomerase as part of the physiologic process of memory formation.<ref name="pmid26052046">{{cite journal | vauthors = Madabhushi R, Gao F, Pfenning AR, Pan L, Yamakawa S, Seo J, Rueda R, Phan TX, Yamakawa H, Pao PC, Stott RT, Gjoneska E, Nott A, Cho S, Kellis M, Tsai LH | display-authors = 6 | title = Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes | journal = Cell | volume = 161 | issue = 7 | pages = 1592–605 | date = June 2015 | pmid = 26052046 | pmc = 4886855 | doi = 10.1016/j.cell.2015.05.032 }}</ref>  DSBs are present in both neurons and astrocytes in the postmortem human [[hippocampus]] of AD patients at a higher level than in non-AD individuals.<ref name = Thadathil2021>{{cite journal | vauthors = Thadathil N, Delotterie DF, Xiao J, Hori R, McDonald MP, Khan MM | title = DNA Double-Strand Break Accumulation in Alzheimer's Disease: Evidence from Experimental Models and Postmortem Human Brains | journal = Molecular Neurobiology | volume = 58 | issue = 1 | pages = 118–131 | date = January 2021 | pmid = 32895786 | doi = 10.1007/s12035-020-02109-8 }}</ref>  AD is associated with an accumulation of DSBs in neurons and astrocytes in the hippocampus and frontal cortex from early stages onward.<ref name="pmid31101070">{{cite journal | vauthors = Shanbhag NM, Evans MD, Mao W, Nana AL, Seeley WW, Adame A, Rissman RA, Masliah E, Mucke L | display-authors = 6 | title = Early neuronal accumulation of DNA double strand breaks in Alzheimer's disease | journal = Acta Neuropathologica Communications | volume = 7 | issue = 1 | pages = 77 | date = May 2019 | pmid = 31101070 | pmc = 6524256 | doi = 10.1186/s40478-019-0723-5 }}</ref> DSBs are increased in the vicinity of amyloid plaques in the hippocampus, indicating a potential role for Aβ in DSB accumulation or vice versa.<ref name = Thadathil2021/>  The predominant mechanism for repairing DNA double-strand breaks is non-homologous end joining (NHEJ), a mechanism that utilizes the DNA-dependent protein kinase (DNA-PK) complex.  The end joining activity and protein levels of DNA-PK catalytic subunit are significantly lower in AD brains than in normal brains.<ref name="pmid15908050">{{cite journal | vauthors = Shackelford DA | title = DNA end joining activity is reduced in Alzheimer's disease | journal = Neurobiology of Aging | volume = 27 | issue = 4 | pages = 596–605 | date = April 2006 | pmid = 15908050 | doi = 10.1016/j.neurobiolaging.2005.03.009 }}</ref>
-==References==
+== References ==
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