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Alzheimer's disease and prions has become a hotly researched topic, where most discoveries focus on explaining interactions within the brain. Prions, which are misfolded proteins, have long been suspected to be correlated with a number of dementia and other neurological diseases. In particular, Alzheimer's disease is hypothesized to be caused by these malforming proteins. Currently, 35 million people suffer from neurological dementia, most of these cases being Alzheimer's Disease, while prion-specific diseases (such as Creutzfeldt-Jakob) affect roughly one million people worldwide.[1] In fact, Alzheimer's Disease may soon overtake cancer as the most prominent cause of loss of life in people older than sixty-five years old.[2] However, the relationship between Alzheimer's Disease and prions is still unfamiliar in many aspects, in particular to what methods can be used to prevent the cause of Alzheimer's Disease.[3]

Normal Brain vs. Alzheimer's Brain
Comparative diagrams of a healthy brain, located on the left, and a brain suffering from Alzheimer's disease. Holes begin to develop in the brain due to shrinkage of the cerebral cortex, and the hippocampus, which plays an important role in memory.
Anatomical terminology

Alzheimer's Disease

Alzheimer's Disease is a form of dementia that results from misfolded proteins, affecting areas in the brain that control short-term memory and emotions. Overall, Alzheimer’s is assumed to affect 30-70% of the 25 million people who suffer from dementia annually.[4] Other clinical symptoms of Alzheimer's Disease include cognitive disfunction, language impairment (both speaking and understanding), and behaviors including paranoia, confusion, hallucinations, and aggression.[5] However, at a neurological level, it is difficult to pinpoint what exactly causes Alzheimer's to develop. Some hypotheses include through brain-created toxins, physical stresses, or even environmental factors, which can cause neuritic plaques called amyloids to form in the brain. Specifically amyloid beta, which causes slow-forming protein aggregates to migrate towards the corticol areas of the brain, can result in degeneration of memory processes.[6] However, there are specific kinds of prions formed, from the amyloid precursor protein (APP) to actual prions (denoted PrPc or PrPSc). The latter designation corresponds to the infectious type of prion, which results in symptoms much like the ones described earlier.[5] However, the biological functions for both APP and PrPc/PrPSc are still not well established.[7]

Prions

Prions are misfolded proteins that can cause serious disorders to occur. This can lead to fatal harm to the brain. The key to these proteins is due to the conformational change, in particular for the secondary structure, which can lead to a “healthy” form of prion (PrPc) and the “unhealthy form” (PrPSc).[8] This unhealthy form of the prion relates more towards Creutzfeldt-Jakob's disease, where essentially the brain shuts down both motor and sensory fuctions within the body, leading to dementia. However, the healthy form (PrPc) merely degrades harmlessly within the body, where the particles are broken down cellularly.[9] Meanwhile, the PrPSc prion can call cross-beta amyloids, which along with the Tau protein can cause a wide set of dementias, including Alzheimer's Disease.[2] Additionally, transmission of prions acts similarly to the transmission of nutrients between cells, although whether through gap junctions or otherwise is still unknown.[2] The gene responsible for coding for prions is the PRNP gene, located on chromosome 20 (out of 46 overall chromosomes).[5][2] Prions have been discovered to be extremely deadly, resulting in diseases such as Parkinson's Disease and Huntington's Disease.[2][10]

Other diseases

Prion disease are often called transmissible spongiform encephalopathies or TSE due to their nature of leaving holes in the brain. One of the earliest forms of TSE's was called Kuru, which involved flesh eating natives who ate brains. This aggressive behavior also led to unstable movement, which raised myths about "impure brains".[9] Mad Cow Disease is very similar to the symptoms of TSE's, where it has its own proper designation, called bovine spongiform encephalopathy or BSE. Creutzfeld-Jakob Disease (CJD) is a genetic form of this disease that results in the same symptoms as kuru. This association however was not made until Carleton Gajdusek, around 1970, studied chimpanzees, injecting them with kuru prions and comparing the results with those obtained from previous documentations of CJD from other researchers.[9] Another disease linked to prions includes Parkinson's Disease, where the substantia nigra is slowly degenerated and dopamine production is reduced. This causes shaky, uncontrollable movements, leading to difficulty in holding objects.[2] Finally, Huntington's Disease, which is also characterized by motor impairment, cognitive decline, and behavioral abnormalities, has been linked to prions as well, where the malformation comes in the Huntington protein, designated HPP.[10]

Amyloid β

Amyloid beta is an amino acid isoform aggregate surrounding the limbic system and axons of the brain.[11][12] This combination of isoform aggregates leads to fibrils assembled from monomeric and oligomeric intermediates.[8] The amyloid precursor protein, mentioned earlier, also plays a strong role in leading to Alzheimer's Disease. This gene is vital in normal brain activity, long-term potentiation, and learning. However, mutations of this gene can lead to cellular stress, depletion of ATP and ischemia.[5] Along with the Tau protein, amyloid beta oligomers can also reduce blood flow, cause lipid oxidation, and form reactive oxygen species or ROS. These oxidative species can reduce the rate of cellular signal transmission and memory retrieval.[7]

Tau protein

The Tau protein is what causes microtubules in brain to destabilize and lead to reduction of brain processes.[8] Additionally, it has been found that Tau can propagate through neuronal networks in the brain, instead of randomly. This is about the extent of what is known about Tau, as questions relating to anatomical connections or whether misfolded aggregates spread cell-to-cell or through extracellular space are still unknown, although suggestions that it can propagate through neuronal synapses are starting to become proven.[3][12] Tau has been found extensively through roughly twenty different forms of dementia, all of which contain these microtubules that inhibit brain processes such as memory or speech from fully functioning.[13]

Genetic factors

As mentioned earlier, the PRNP gene, located on chromosome 20, is one of the causes of misfolded proteins, although at a primary level (i.e. amino acids), there isn't clear information about the creation of prions. However, constant apoptosis and necrosis are both cellular effects that result from prions. In particular, activation of caspase 3, an enzyme involved in apoptosis, becomes stimulated and over-programs cellular suicide.[5][14]

Current research

A lot of current research still focuses at an in vitro level. The actual treatment research focus is very little, where instead there is a concentration on ameliorating symptoms.[2][15] However, given the number of unknowns facing prions and the resulting amyloids, this is perhaps an already strong stage of research. Additionally, some certain amino acid sequences have been detected, specifically with the usage of glutamine, an amino acid involved in creating cellular structure.[2] Additionally, it is largely unknown about prion cellular transfer and how toxicity results in specific cell degeneration. There have been current developments that Tau protein can be transmitted through certain pathways, in the cerebrospinal fluid, blood, and potentially across synapses, which could provide a model for prion transport.[3] However, most research is still focused on linking amyloid beta to tau proteins, as a result of the PrPSc infectious prions.[4][11][12]

Treatment strategies

Treatments for prion diseases have been difficult, mainly due to the focus on preventing them from reaching a misfolded state. Quinacrine is one of the drugs that has been used as a treatment, but the continued difficulty for quinacrine to accumulate in the brain has led to it being ineffective in vivo. This is mainly due to the challenge of crossing the blood-brain barrier.[16] Interestingly enough, quinacrine does allow for cells to dispose of PrPSc on their own. The precursor for quinacrine was chlorpromazine, an anti-malarial drug developed in 1876, derived from methylene blue.It functions the same way as quinacrine, but at about one-tenth the rate of reducing PrPSc.[9][17] Other compounds are still under clinical trials, but the proposed structure for the basic multivalent antiprion compound consists of a quinoline or acridine ring, linked via tethers in a planar aromatic structure. This structure encompasses sulfated glycans or other compounds, such as trimesic acid, which can also bind to PrPSc prions without affecting cell viability.[18]

Future testing and research

Future testing treatments are still focused on mammals, especially mice and pigs.[9][10][18] These models, along with any prions found, should lead to ideal results for clinical trials in humans. Other methods of research look at simple, unicellular organisms, focusing on similarities and differences in prions, amyloids, and even Tau protein between species. For example, amyloid beta does not seem to present itself in yeast, which signals that perhaps it is restricted to human brain production only.[2] Other areas of research revolve around creating a sort of blocking mechanism for certain amino acid sequences, such as the glutamine sequences mentioned earlier, to prevent infectious prions from forming. However, not a lot of research is known about these specific interactions.[2] Finally, recent research has indicated that derivatives of quinacrine and chlorpromazine can be used to study rRNA, and its potential role in forming PrPSc prions through competitive binding to rRNA.[19]

See also

References

  1. ^ Galdeano, C., Viayna, E., Sola, I., Formosa, X., Camps, P., Badia, A., . . . Munoz-Torrero, D. (2012). Huprine-tacrine heterodimers as anti-amyloidogenic compounds of potential interest against Alzheimer's and prion diseases. [Research Support, Non-U.S. Gov't]. J Med Chem, 55(2), 661-669. doi: 10.1021/jm200840c
  2. ^ a b c d e f g h i j Liebman, S. W., & Chernoff, Y. O. (2012). Prions in yeast. [Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.]. Genetics, 191(4), 1041-1072. doi: 10.1534/genetics.111.137760
  3. ^ a b c Hall, G. F., & Patuto, B. A. (2012). Is tau ready for admission to the prion club? Prion, 6(3), 223-233. doi: 10.4161/pri.19912
  4. ^ a b Wolf, L. K. (2012). Alzheimer's Prion Connection. Chemical & Engineering News, 90(27), 24-26.
  5. ^ a b c d e Dias Bda, C., Jovanovic, K., Gonsalves, D., & Weiss, S. F. (2011). Structural and mechanistic commonalities of amyloid-beta and the prion protein. [Research Support, Non-U.S. Gov't Review]. Prion, 5(3), 126-137. doi: 10.4161/pri.5.3.17025
  6. ^ Miyazawa, K., Kipkorir, T., Tittman, S., & Manuelidis, L. (2012). Continuous production of prions after infectious particles are eliminated: implications for Alzheimer's disease. [Research Support, N.I.H., Extramural]. PLoS One, 7(4), e35471. doi: 10.1371/journal.pone.0035471
  7. ^ a b Brown, D. R., & Kozlowski, H. (2004). Biological inorganic and bioinorganic chemistry of neurodegeneration based on prion and Alzheimer diseases. [Research Support, Non-U.S. Gov'tReview]. Dalton Trans(13), 1907-1917. doi: 10.1039/b401985g
  8. ^ a b c Nussbaum, J. M., Schilling, S., Cynis, H., Silva, A., Swanson, E., Wangsanut, T., . . . Bloom, G. S. (2012). Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-beta. Nature, 485(7400), 651-655. doi: Doi 10.1038/Nature11060
  9. ^ a b c d e Yam, Philip. The Pathological Protein: Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases. New York: Copernicus, 2003. Print.
  10. ^ a b c Gupta, S., Jie, S., & Colby, D. W. (2012). Protein misfolding detected early in pathogenesis of transgenic mouse model of Huntington disease using amyloid seeding assay. [Research Support, N.I.H., Extramural]. J Biol Chem, 287(13), 9982-9989. doi: 10.1074/jbc.M111.305417
  11. ^ a b Zhao, L. N., Long, H. W., Mu, Y. G., & Chew, L. Y. (2012). The Toxicity of Amyloid beta Oligomers. International Journal of Molecular Sciences, 13(6), 7303-7327. doi: Doi 10.3390/Ijms13067303
  12. ^ a b c Kfoury, N., Holmes, B. B., Jiang, H., Holtzman, D. M., & Diamond, M. I. (2012). Trans-cellular propagation of Tau aggregation by fibrillar species. [Research Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't]. J Biol Chem, 287(23), 19440-19451. doi: 10.1074/jbc.M112.346072
  13. ^ Saman, S., Kim, W., Raya, M., Visnick, Y., Miro, S., Saman, S., . . . Hall, G. F. (2012). Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, Non-P.H.S.]. J Biol Chem, 287(6), 3842-3849. doi: 10.1074/jbc.M111.277061
  14. ^ Johanssen, V. A., Barnham, K. J., Masters, C. L., Hill, A. F., & Collins, S. J. (2012). Generating recombinant C-terminal prion protein fragments of exact native sequence. [Research Support, Non-U.S. Gov't]. Neurochem Int, 60(3), 318-326. doi: 10.1016/j.neuint.2011.12.006
  15. ^ Gonsalves, D., Jovanovic, K., Da Costa Dias, B., & Weiss, S. F. (2012). Global Alzheimer Research Summit: basic and clinical research: present and future Alzheimer research. [CongressesResearch Support, Non-U.S. Gov't]. Prion, 6(1), 7-10. doi: 10.4161/pri.6.1.18854
  16. ^ Ghaemmaghami, S., Ahn, M., Lessard, P., Giles, K., Legname, G., DeArmond, S. J., & Prusiner, S. B. (2009). Continuous quinacrine treatment results in the formation of drug-resistant prions. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't]. PLoS Pathog, 5(11), e1000673. doi: 10.1371/journal.ppat.1000673
  17. ^ Orrù, C. D., Cannas, M. D., Vascellari, S., Angius, F., Cocco, P. L., Norfo, C., . . . Pani, A. (2010). In vitro synergistic anti-prion effect of cholesterol ester modulators in combination with chlorpromazine and quinacrine. Central European Journal of Biology, 5(2), 151-165. doi: 10.2478/s11535-009-0070-9
  18. ^ a b Mays, C. E., Joy, S., Li, L., Yu, L., Genovesi, S., West, F. G., & Westaway, D. (2012). Prion inhibition with multivalent PrPSc binding compounds. [Research Support, Non-U.S. Gov't]. Biomaterials, 33(28), 6808-6822. doi: 10.1016/j.biomaterials.2012.06.004
  19. ^ Gug, F., Oumata, N., Tribouillard-Tanview, D., Voisset, C., Desban, N., Bach, S., Blondel, M., & Galons, H. (2010). Synthesis of Conjugates of 6-Aminophenanthridine and Guanabenz, Two Structurall Unrelated Prion Inhibitors, for the Determination of Their Cellular Targets by Affinity Chromatography. Bioconjugate Chem., 21, 279-288.
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