Beta amyloid

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Beta-amyloid peptide (beta-APP)
Abeta 2lfm.jpg
A partially folded structure of amyloid-beta(1 40) in an aqueous environment (pdb 2lfm)[1]
Identifiers
Symbol APP
Pfam PF03494
InterPro IPR013803
SCOP 2lfm
SUPERFAMILY 2lfm
TCDB 1.C.50
OPM superfamily 369
OPM protein 2y3k
amyloid-beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)
APP processing.png
Processing of the amyloid precursor protein
Identifiers
Symbol APP
Alt. symbols AD1
Entrez 351
HUGO 620
OMIM 104760
RefSeq NM_000484
UniProt P05067
Other data
Locus Chr. 21 q21.2

Amyloid-beta ( or Abeta) denotes peptides of 36–43 amino acids that are crucially involved in Alzheimer's disease as the main component of the amyloid plaques found in the brains of Alzheimer patients. The peptides result from the amyloid precursor protein (APP), which is being cut by certain enzymes to yield Aβ. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers (known as "seeds") can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The seeds or the resulting amyloid plaques are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.[2]

A recent study suggested that APP and its amyloid potential is of ancient origins, dating as far back as early deuterostomes.[3]

Normal activity[edit]

The normal function of Aβ is not well understood.[4] Though some animal studies have shown that the absence of Aβ does not lead to any loss of physiological function,[5][6] several potential activities have been discovered for Aβ, including activation of kinase enzymes,[7][8] protection against oxidative stress,[9][10] regulation of cholesterol transport,[11][12] functioning as a transcription factor,[13][14] and anti-microbial activity (potentially associated with Aβ's pro-inflammatory activity).[15]

The glymphatic system clears metabolic waste from the mammalian brain, and in particular beta amyloids.[16] The rate of removal is significantly increased during sleep.[17]

Disease associations[edit]

Aβ is the main component of amyloid plaques (extracellular deposits found in the brains of patients with Alzheimer's disease). Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis (a muscle disease), while Aβ can also form the aggregates that coat cerebral blood vessels in cerebral amyloid angiopathy. The plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibers,[18] a protein fold shared by other peptides such as the prions associated with protein misfolding diseases. Recent research suggests that soluble oligomeric forms of the peptide may be causative agents in the development of Alzheimer's disease.[19][20] It is generally believed that Aβ oligomers are the most toxic.[21] A number of genetic, cell biology, biochemical and animal studies support the concept that Aβ plays a central role in the development of Alzheimer’s disease pathology.[22][23]

Brain Aβ is elevated in patients with sporadic Alzheimer’s disease. Aβ is the main constituent of brain parenchymal and vascular amyloid; it contributes to cerebrovascular lesions and is neurotoxic.[22][23][24][25] It is unresolved how Aβ accumulates in the central nervous system and subsequently initiates the disease of cells. Some researchers have found that the Aβ oligomers induce some of the symptoms of Alzheimer's Disease by competing with insulin for binding sites on the insulin receptor, thus impairing glucose metabolism in the brain.[26] Significant efforts have been focused on the mechanisms responsible for Aβ production, including the proteolytic enzymes alpha- and β-secretases which generate Aβ from its precursor protein, APP (amyloid precursor protein).[27][28][29][30] Aβ circulates in plasma, cerebrospinal fluid (CSF) and brain interstitial fluid (ISF) mainly as soluble Aβ40[22][31] Senile plaques contain both Aβ40 and Aβ42,[32] while vascular amyloid is predominantly the shorter Aβ40. Several sequences of Aβ were found in both lesions.[33][34][35] Generation of Aβ in the CNS may take place in the neuronal axonal membranes after APP-mediated axonal transport of β-secretase and presenilin-1.[36]

Increases in either total Aβ levels or the relative concentration of both Aβ40 and Aβ42 (where the former is more concentrated in cerebrovascular plaques and the latter in neuritic plaques)[37] have been implicated in the pathogenesis of both familial and sporadic Alzheimer's disease. Due to its more hydrophobic nature, the Aβ42 is the most amyloidogenic form of the peptide. However the central sequence KLVFFAE is known to form amyloid on its own, and probably forms the core of the fibril.

The "amyloid hypothesis", that the plaques are responsible for the pathology of Alzheimer's disease, is accepted by the majority of researchers but is by no means conclusively established. An alternative hypothesis is that amyloid oligomers rather than plaques are responsible for the disease.[21][38] Mice that are genetically engineered to express oligomers but not plaques (APPE693Q) develop the disease. Furthermore mice that are in addition engineered to convert oligomers into plaques (APPE693Q X PS1ΔE9), are no more impaired than the oligomer only mice.[39] Intra-cellular deposits of tau protein are also seen in the disease, and may also be implicated, as has aggregation of alpha synuclein.

Formation[edit]

Aβ is formed after sequential cleavage of the amyloid precursor protein (APP), a transmembrane glycoprotein of undetermined function. APP can be cleaved by the proteolytic enzymes α-, β- and γ-secretase; Aβ protein is generated by successive action of the β and γ secretases. The γ secretase, which produces the C-terminal end of the Aβ peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 36-43 amino acid residues in length. The most common isoforms are Aβ40 and Aβ42; the longer form is typically produced by cleavage that occurs in the endoplasmic reticulum, while the shorter form is produced by cleavage in the trans-Golgi network.[40] The Aβ40 form is the more common of the two, but Aβ42 is the more fibrillogenic and is thus associated with disease states. Mutations in APP associated with early-onset Alzheimer's have been noted to increase the relative production of Aβ42, and thus one suggested avenue of Alzheimer's therapy involves modulating the activity of β and γ secretases to produce mainly Aβ40.[41] Aβ is destroyed by several amyloid-degrading enzymes including neprilysin.[42]

Genetics[edit]

Autosomal-dominant mutations in APP cause hereditary early-onset Alzheimer's disease (a.k.s. familial AD). This form of AD accounts for no more than 10% of all cases, and the vast majority of AD is not accompanied by such mutations.[43] However, familial Alzheimer disease is likely to result from altered proteolytic processing.

The gene for amyloid precursor protein is located on chromosome 21, and accordingly patients with trisomy 21 (Down's syndrome) have a very high incidence of Alzheimer's disease.

Structure and Toxicity[edit]

Amyloid beta is commonly thought to be intrinsically unstructured, meaning that in solution it does not acquire a unique tertiary fold but rather populates a set of structures. As such, it cannot be crystallized and most structural knowledge on amyloid beta comes from NMR and molecular dynamics. Early NMR-derived models of a 26-aminoacid polypeptide from amyloid beta (Aβ 10-35) show a collapsed coil structure devoid of significant secondary structure content,[44] however, the most recent (2012) NMR structure of (Aβ 1-40) has significant secondary and tertiary structure.[1] Replica exchange molecular dynamics studies suggested that amyloid beta can indeed populate multiple discrete structural states;[45] more recent studies identified a multiplicity of discrete conformational clusters by statistical analysis.[46] By NMR-guided simulations, amyloid beta 1-40 and amyloid beta 1-42 also seem to feature highly different conformational states,[47] with the C-terminus of amyloid beta 1-42 being more structured than that of the 1-40 fragment.

Structural information on the oligomeric state of amyloid beta is still sparse as of 2010. Low-temperature and low-salt conditions allowed to isolate pentameric disc-shaped oligomers devoid of beta structure.[48] In contrast, soluble oligomers prepared in the presence of detergents seem to feature substantial beta sheet content with mixed parallel and antiparallel character, different from fibrils;[49] computational studies suggest an antiparallel beta-turn-beta motif instead for membrane-embedded oligomers.[50]

The mechanism by which amyloid beta may damage and kill neurons is by generating reactive oxygen species during the process of its self-aggregation. When this occurs on the membrane of neurons it causes lipid peroxidation and the generation of a toxic aldehyde called 4-hydroxynonenal which, in turn, impairs the function of ion-motive ATPases, glucose transporters and glutamate transporters. As a result of amyloid beta promotes depolarization of the synaptic membrane, excessive calcium influx and mitochondrial impairment.[51]

Intervention strategies[edit]

Researchers in Alzheimer's disease have identified five strategies as possible interventions against amyloid:[52]

  • β-Secretase inhibitors. These work to block the first cleavage of APP outside of the cell.
  • γ-Secretase inhibitors (e. g. semagacestat). These work to block the second cleavage of APP in the cell membrane and would then stop the subsequent formation of Aβ and its toxic fragments.
  • Selective Aβ42 lowering agents (e. g. tarenflurbil). These modulate γ-secretase to reduce Aβ42 production in favor of other (shorter) Aβ versions.

β- and γ-secretase are responsible for the generation of Aβ from the release of the intracellular domain of APP, meaning that compounds that can partially inhibit the activity of either β- and γ-secretase are highly sought after. In order to initiate partial inhibition of β- and γ-secretase, a compound is needed that can block the large active site of aspartyl proteases while still being capable of bypassing the blood-brain barrier. To date, human testing has been avoided due to concern that it might interfere with signaling via Notch proteins and other cell surface receptors.

  • Immunotherapy. This stimulates the host immune system to recognize and attack Aβ, or provide antibodies that either prevent plaque deposition or enhance clearance of plaques or Aβ oligomers. Oligomerization is a chemical process that converts individual molecules into a chain consisting of a finite number of molecules. Prevention of oligomerization of Aβ has been exemplified by active or passive Aβ immunization. In this process antibodies to Aβ are used to decrease cerebral plaque levels. This is accomplished by promoting microglial clearance and/or redistributing the peptide from the brain to systemic circulation. One such beta-amyloid vaccine that is currently in clinical trials is CAD106.[53] Immunization with synthetic Aβ1-42 has been shown to be beneficial in mice and displays low toxicity; however human trials have shown no significant differences. Thus, it is not yet effective in humans and requires further research. Specific findings show that the 20 amino acid SDPM1 protein binds tetramer forms of Aβ(1-40)- and Aβ(1-42)-amyloids and blocks subsequent Aβ amyloid aggregation. It is important to note that this study was done in mice and that while it prevents further development of neuropathology it did not result in an improvement in cognitive performance. Lastly, Aβ42 immunization resulted in the clearance of amyloid plaques in patients with Alzheimer's disease but did not prevent progressive neurodegeneration.[54]
  • Anti-aggregation agents[55] such as apomorphine. These prevent Aβ fragments from aggregating or clear aggregates once they are formed.[56] Studies comparing synthetic to recombinant Aβ42 in assays measuring rate of fibrillation, fibril homogeneity, and cellular toxicity showed that recombinant Aβ42 had a faster fibrillation rate and greater toxicity than synthetic Amyloid beta 1-42 peptide.[57] This observation combined with the irreproducibility of certain Aβ42 experimental studies has been suggested to be responsible for the lack of progress in Alzheimer’s research.[58] Consequently, there has been renewed efforts to manufacture Aβ42 and other amyloid peptides at unprecedented (>99%) purity[59]

There is some indication that supplementation of the hormone melatonin may be effective against amyloid. Melatonin interacts with amyloid beta and inhibits its aggregation[60][61][62] This anti-aggregatory activity occurs only through an interaction with dimers of the soluble amyloid beta peptide. Melatonin does not reverse fibril formation or oligomers of amyloid beta once they are formed. This is supported by experiments in transgenic mice which suggest that melatonin has the potential to prevent amyloid deposition if administered early in life, but it may not be efficacious to revert amyloid deposition or treat Alzheimer's disease.

This connection with melatonin, which regulates sleep, is strengthened by the recent research showing that the wakefulness inducing hormone orexin influences amyloid beta (see below).[63] Interestingly, animal experiments show that melatonin may also correct mild elevations of cholesterol which is also an early risk factor for amyloid formation.

The cannabinoid HU-210 has been shown to prevent amyloid beta-promoted inflammation.[64] The endocannabinoids anandamide and noladin ether have also been shown to be neuroprotective against amyloid beta in vitro.[65]

It has been shown that high-cholesterol diets tend to increase Aβ pathology in animals. Modulating cholesterol homeostasis has yielded results that show that chronic use of cholesterol-lowering drugs, such as the statins, is associated with a lower incidence of AD. In APP genetically modified mice, cholesterol-lowering drugs have been shown to reduce overall pathology. While the mechanism is poorly understood it appears that cholesterol-lowering drugs have a direct effect on APP processing.[66]

Chelation therapy, which involves the removal of heavy metals from the body, has also been shown to be beneficial in lowering amyloid plaque levels. This is because Aβ aggregation is somewhat dependent on the metal ions copper and zinc. Zinc in synaptic vesicles, which is under the control of the zinc transporter ZnT3, plays a major role in Aβ formation. The expression of the ZnT3 is significantly lower in Alzheimer’s patients compared to healthy patients. Mice without ZnT3 were found to have much lower plaque formation. Further promoting this concept, Aβ deposition was impeded in APP transgenic mice treated with the antibiotic clioquinol, a known copper/zinc chelator.[66]

Drug therapy has been another approach to treatment. Memantine is an Alzheimer’s drug which has received widespread approval. It is a non-competitive N-methyl-D-aspartate (NMDA) channel blocker. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. It is an option for the management of patients with moderate to severe Alzheimer's Disease (modest effect). The study showed that 20 mg/day improved cognition, functional ability and behavioural symptoms in patient population.[67]

Another drug that is currently under research is victoza, which is typically used as a diabetes drug. Treatment with victoza yielded cognitive benefits that included improved object and spatial recognition. Additionally victoza enhances induction and maintenance of long term potentiation (LTP) and paired-pulse facilitation (PPF) in both APP/PS1 and non-genetically altered mice. Other histological benefits include a reduced inflammatory response and an increase in the number of young neurons in the dentate gyrus. The β-amyloid level was also found to be significantly reduced.[68]

Circadian rhythm of amyloid beta[edit]

A 2009 report demonstrated that amyloid beta production follows a circadian rhythm, rising when an animal (mouse) or person is awake and falling during sleep.[63] The wakefulness-promoting neuroprotein orexin was shown to be necessary for the circadian rhythm of amyloid beta production.[63] The report suggested that excessive periods of wakefulness (i.e. due to sleep debt) could cause chronic build-up of amyloid beta, which could hypothetically lead to Alzheimer's disease.[63] This is consistent with recent findings that chronic sleep deprivation is associated with early onset Alzheimer's disease.[63]

Melatonin is also involved in circadian rhythm maintenance. Notably, melatonin has been connected with the "sundowning" phenomenon, in which Alzheimer's disease patients that have amyloid plaques in the hypothalamus exhibit exacerbation of Alzheimer's disease symptoms late in the day.[69] This "sundowning" phenomenon could be directly or indirectly related to the recently discovered continuous increase in amyloid beta throughout the day.

Measuring amyloid beta[edit]

Micrograph showing amyloid beta (brown) in senile plaques of the cerebral cortex (upper left of image) and cerebral blood vessels (right of image) with immunostaining.

There are many different ways to measure Amyloid beta. It can be measured semi-quantitatively with immunostaining, which also allows one to determine location. Amyloid beta may be primarily vascular, as in cerebral amyloid angiopathy, or in senile plaques and vascular.

One highly sensitive method is ELISA which is an immunosorbent assay which utilizes a pair of antibodies that recognize Amyloid beta.[70][71]

Imaging compounds, notably Pittsburgh compound B, (6-OH-BTA-1, a thioflavin), can selectively bind to amyloid beta in vitro and in vivo. This technique, combined with PET imaging, has been used to image areas of plaque deposits in Alzheimer's patients.

Atomic force microscopy, which can visualize nanoscale molecular surfaces, can be used to determine the aggregation state of Amyloid beta in vitro.[72]

Dual polarisation interferometry is an optical technique which can measure the very earliest stages of aggregration and inhibition by measuring the molecular size and densities as the fibrils elongate.[73][74] These aggregate processes can also be studied on lipid bilayer constructs.[75]

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