Amyloid beta

Amyloid beta (Aβ 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 people with Alzheimer's disease.[2] The peptides derive from the amyloid precursor protein (APP), which is cleaved by beta secretase and gamma secretase 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 oligomers are toxic to nerve cells.[3] 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.[4][5]

Amyloid beta peptide (beta-APP)
A partially folded structure of amyloid beta(1 40) in an aqueous environment (pdb 2lfm)[1]
Identifiers
SymbolAPP
PfamPF03494
InterProIPR013803
SCOPe2lfm / SUPFAM
TCDB1.C.50
OPM superfamily304
OPM protein2y3k
Membranome45
amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)
Processing of the amyloid precursor protein
Identifiers
SymbolAPP
Alt. symbolsAD1
NCBI gene351
HGNC620
OMIM104760
RefSeqNM_000484
UniProtP05067
Other data
LocusChr. 21 q21.2

A study has suggested that APP and its amyloid potential is of ancient origins, dating as far back as early deuterostomes.[6]

Normal function

The normal function of Aβ is not well understood.[7] Though some animal studies have shown that the absence of Aβ does not lead to any obvious loss of physiological function,[8][9] several potential activities have been discovered for Aβ, including activation of kinase enzymes,[10][11] protection against oxidative stress,[12][13] regulation of cholesterol transport,[14][15] functioning as a transcription factor,[16][17] and anti-microbial activity (potentially associated with Aβ's pro-inflammatory activity).[18][19][20]

The glymphatic system clears metabolic waste from the mammalian brain, and in particular beta amyloids.[21] Indeed, a number of proteases have been implicated by both genetic and biochemical studies as being responsible for the recognition and degradation of beta amyloids; these include insulin degrading enzyme.[22] and presequence protease[23] The rate of removal is significantly increased during sleep.[24] However, the significance of the lymphatic system in Aβ clearance in Alzheimer's disease is unknown.[25]

Disease associations

Aβ is the main component of amyloid plaques (extracellular deposits found in the brains of patients with Alzheimer's disease).[26] 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,[27] a protein fold shared by other peptides such as the prions associated with protein misfolding diseases.

Alzheimer's disease

Research suggests that soluble oligomeric forms of the peptide may be causative agents in the development of Alzheimer's disease.[28][29] It is generally believed that Aβ oligomers are the most toxic.[30] The ion channel hypothesis postulates that oligomers of soluble, non-fibrillar Aβ form membrane ion channels allowing the unregulated calcium influx into neurons[31] that underlies disrupted calcium ion homeostasis and apoptosis seen in Alzheimer's disease.[32][33] Computational studies have demonstrated that also Aβ peptides embedded into the membrane as monomers with predominant helical configuration, can oligomerize[34] and eventually form channels whose stability and conformation are sensitively correlated to the concomitant presence and arrangement of cholesterol.[35] 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.[36][37]

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.[36][37][38][39] 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.[40] Significant efforts have been focused on the mechanisms responsible for Aβ production, including the proteolytic enzymes gamma- and β-secretases which generate Aβ from its precursor protein, APP (amyloid precursor protein).[41][42][43][44] Aβ circulates in plasma, cerebrospinal fluid (CSF) and brain interstitial fluid (ISF) mainly as soluble Aβ40[36][45] Senile plaques contain both Aβ40 and Aβ42,[46] while vascular amyloid is predominantly the shorter Aβ40. Several sequences of Aβ were found in both lesions.[47][48][49] Generation of Aβ in the central nervous system may take place in the neuronal axonal membranes after APP-mediated axonal transport of β-secretase and presenilin-1.[50]

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)[51] 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. One study further correlated Aβ42 levels in the brain not only with onset of Alzheimer's disease, but also reduced cerebrospinal fluid pressure, suggesting that a build-up or inability to clear Aβ42 fragments may play a role into the pathology.[52]

The "amyloid hypothesis", that the plaques are responsible for the pathology of Alzheimer's disease, is accepted by the majority of researchers but is not conclusively established. An alternative hypothesis is that amyloid oligomers rather than plaques are responsible for the disease.[30][53] 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.[54] Intra-cellular deposits of tau protein are also seen in the disease, and may also be implicated, as has aggregation of alpha synuclein.

Cancer

While Aβ has been implicated in cancer development, prompting studies on a variety of cancers to elucidate the nature of its possible effects, results are largely inconclusive. Aβ levels have been assessed in relation to a number of cancers, including esophageal, colorectal, lung, and hepatic, in response to observed reductions in risk for developing Alzheimer's disease in survivors of these cancers. All cancers were shown to be associated positively with increased Aβ levels, particularly hepatic cancers.[55] This direction of association however has not yet been established. Studies focusing on human breast cancer cell lines have further demonstrated that these cancerous cells display an increased level of expression of amyloid precursor protein.[56]

Down Syndrome

Adults with Down syndrome had accumulation of amyloid in association with evidence of Alzheimer's disease, including declines in cognitive functioning, memory, fine motor movements, executive functioning, and visuospatial skills.[57]

Formation

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 30-51 amino acid residues in length.[58] 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.[59]

Genetics

Autosomal-dominant mutations in APP cause hereditary early-onset Alzheimer's disease (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.[60] However, familial Alzheimer's disease is likely to result from altered proteolytic processing.

The gene for the amyloid precursor protein is located on chromosome 21, and accordingly people with Down syndrome have a very high incidence of Alzheimer's disease.[61]

Structure and toxicity

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.[62] 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;[63] more recent studies identified a multiplicity of discrete conformational clusters by statistical analysis.[64] By NMR-guided simulations, amyloid beta 1-40 and amyloid beta 1-42 also seem to feature highly different conformational states,[65] with the C-terminus of amyloid beta 1-42 being more structured than that of the 1-40 fragment.

Low-temperature and low-salt conditions allowed to isolate pentameric disc-shaped oligomers devoid of beta structure.[66] 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;[67] computational studies suggest an antiparallel beta-turn-beta motif instead for membrane-embedded oligomers.[68]

The suggested mechanisms by which amyloid beta may damage and cause neuronal death include the generation of reactive oxygen species during the process of its self-aggregation. When this occurs on the membrane of neurons in vitro, 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, amyloid beta promotes depolarization of the synaptic membrane, excessive calcium influx and mitochondrial impairment.[69] Aggregations of the amyloid-beta peptide disrupt membranes in vitro.[70]

Intervention strategies
Further information: Alzheimer's disease § Research directions

Researchers in Alzheimer's disease have identified several strategies as possible interventions against amyloid:[71]

  • β-Secretase inhibitors. These work to block the first cleavage of APP inside of the cell, at the endoplasmic reticulum.
  • 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. Antibodies that target Aβ that currently in clinical trials included aducanumab, bapineuzumab, crenezumab, gantenerumab, gantenerumab, and solanezumab.[72][73] Beta-amyloid vaccines that are currently in clinical trials include CAD106 and UB-311.[72] However literature reviews have raised questions as to immunotherapy's overall efficacy. One such study assessing ten anti-Ab42 antibodies showed minimal cognitive protection and results within each trial, as symptoms were too far progressed by the time of application to be useful. Further development is still required for application to presymptomatic patients to assess their effectiveness early into disease progression.[74]
  • Anti-aggregation agents[75] such as apomorphine, or carbenoxolone. The latter has commonly been used as a treatment for peptic ulcers, but also displays neuroprotective properties, shown to improve cognitive functions such as verbal fluency and memory consolidation. By binding with high affinity to Aβ42 fragments, primarily via hydrogen bonding, carbenoxolone captures the peptides before they can aggregate together, rendering them inert, as well as destabilizes those aggregates already formed, helping to clear them.[76] This is a common mechanism of action of anti-aggregation agents at large.[77]
  • 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.[78][79]
  • 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.[80][81]
  • Memantine is an Alzheimer's disease 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.[82]
  • Norvaline is a candidate drug for the treatment of Alzheimer's disease. It is an arginase inhibitor which readily crosses the blood brain barrier, and reduces arginine loss in the brain. Amyloid beta deposition is associated with L-arginine deprivation and neurodegeneration. Mice treated with Norvaline display improved spatial memory, increased neuroplasticity-related proteins, and decrease in amyloid beta.[83]

Measuring amyloid beta
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.

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, is used to image areas of plaque deposits in Alzheimer's patients.[84]

Post mortem or in tissue biopsies

Amyloid beta can be measured semiquantitatively with immunostaining, which also allows one to determine location. Amyloid beta may be primarily vascular, as in cerebral amyloid angiopathy, or in senile plaques in white matter.[85]

One sensitive method is ELISA which is an immunosorbent assay which utilizes a pair of antibodies that recognize amyloid beta.[86][87]

Atomic force microscopy, which can visualize nanoscale molecular surfaces, can be used to determine the aggregation state of amyloid beta in vitro.[88]

Dual polarisation interferometry is an optical technique which can measure early stages of aggregation by measuring the molecular size and densities as the fibrils elongate.[89][90] These aggregate processes can also be studied on lipid bilayer constructs.[91]

gollark: So actually lots of them are sensible but some of them are just really bad.
gollark: `collections` is okayish maybe, right?
gollark: Suuuuuuure it is.
gollark: yes.
gollark: Stackless Python and pypy probably do.

See also

References
  1. Vivekanandan S, Brender JR, Lee SY, Ramamoorthy A (July 2011). "A partially folded structure of amyloid-beta(1-40) in an aqueous environment". Biochemical and Biophysical Research Communications. 411 (2): 312–6. doi:10.1016/j.bbrc.2011.06.133. PMC 3148408. PMID 21726530.
  2. Hamley IW (October 2012). "The Amyloid Beta Peptide: A Chemist's Perspective. Role in Alzheimer's and Fibrillization" (PDF). Chemical Reviews. 112 (10): 5147–92. doi:10.1021/cr3000994. PMID 22813427.
  3. Haass C, Selkoe DJ (February 2007). "Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide". Nature Reviews. Molecular Cell Biology. 8 (2): 101–12. doi:10.1038/nrm2101. PMID 17245412.
  4. Nussbaum JM, Seward ME, Bloom GS (Jan–Feb 2013). "Alzheimer disease: a tale of two prions". Prion. 7 (1): 14–9. doi:10.4161/pri.22118. PMC 3609044. PMID 22965142.
  5. Pulawski W, Ghoshdastider U, Andrisano V, Filipek S (April 2012). "Ubiquitous amyloids". Applied Biochemistry and Biotechnology. 166 (7): 1626–43. doi:10.1007/s12010-012-9549-3. PMC 3324686. PMID 22350870.
  6. Tharp WG, Sarkar IN (April 2013). "Origins of amyloid-β". BMC Genomics. 14 (1): 290. doi:10.1186/1471-2164-14-290. PMC 3660159. PMID 23627794.
  7. Hiltunen M, van Groen T, Jolkkonen J (2009). "Functional roles of amyloid-beta protein precursor and amyloid-beta peptides: evidence from experimental studies". Journal of Alzheimer's Disease. 18 (2): 401–12. doi:10.3233/JAD-2009-1154. PMID 19584429.
  8. Sadigh-Eteghad S, Talebi M, Farhoudi M, EJ Golzari S, Sabermarouf B, Mahmoudi J (2014). "Beta-amyloid exhibits antagonistic effects on alpha 7 nicotinic acetylcholine receptors in orchestrated manner". Journal of Medical Hypotheses and Ideas. 8 (2): 48–52. doi:10.1016/j.jmhi.2014.01.001.
  9. Luo Y, Bolon B, Damore MA, Fitzpatrick D, Liu H, Zhang J, et al. (October 2003). "BACE1 (beta-secretase) knockout mice do not acquire compensatory gene expression changes or develop neural lesions over time". Neurobiology of Disease. 14 (1): 81–8. doi:10.1016/S0969-9961(03)00104-9. PMID 13678669.
  10. Bogoyevitch MA, Boehm I, Oakley A, Ketterman AJ, Barr RK (March 2004). "Targeting the JNK MAPK cascade for inhibition: basic science and therapeutic potential". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1697 (1–2): 89–101. doi:10.1016/j.bbapap.2003.11.016. PMID 15023353.
  11. Tabaton M, Zhu X, Perry G, Smith MA, Giliberto L (January 2010). "Signaling effect of amyloid-beta(42) on the processing of AβPP". Experimental Neurology. 221 (1): 18–25. doi:10.1016/j.expneurol.2009.09.002. PMC 2812589. PMID 19747481.
  12. Zou K, Gong JS, Yanagisawa K, Michikawa M (June 2002). "A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage". The Journal of Neuroscience. 22 (12): 4833–41. doi:10.1523/JNEUROSCI.22-12-04833.2002. PMC 6757724. PMID 12077180.
  13. Baruch-Suchodolsky R, Fischer B (May 2009). "Abeta40, either soluble or aggregated, is a remarkably potent antioxidant in cell-free oxidative systems". Biochemistry. 48 (20): 4354–70. doi:10.1021/bi802361k. PMID 19320465.
  14. Yao ZX, Papadopoulos V (October 2002). "Function of beta-amyloid in cholesterol transport: a lead to neurotoxicity". FASEB Journal. 16 (12): 1677–9. doi:10.1096/fj.02-0285fje. PMID 12206998.
  15. Igbavboa U, Sun GY, Weisman GA, He Y, Wood WG (August 2009). "Amyloid beta-protein stimulates trafficking of cholesterol and caveolin-1 from the plasma membrane to the Golgi complex in mouse primary astrocytes". Neuroscience. 162 (2): 328–38. doi:10.1016/j.neuroscience.2009.04.049. PMC 3083247. PMID 19401218.
  16. Maloney B, Lahiri DK (November 2011). "The Alzheimer's amyloid β-peptide (Aβ) binds a specific DNA Aβ-interacting domain (AβID) in the APP, BACE1, and APOE promoters in a sequence-specific manner: characterizing a new regulatory motif". Gene. 488 (1–2): 1–12. doi:10.1016/j.gene.2011.06.004. PMC 3381326. PMID 21699964.
  17. Bailey JA, Maloney B, Ge YW, Lahiri DK (November 2011). "Functional activity of the novel Alzheimer's amyloid β-peptide interacting domain (AβID) in the APP and BACE1 promoter sequences and implications in activating apoptotic genes and in amyloidogenesis". Gene. 488 (1–2): 13–22. doi:10.1016/j.gene.2011.06.017. PMC 3372404. PMID 21708232.
  18. Kagan BL, Jang H, Capone R, Teran Arce F, Ramachandran S, Lal R, Nussinov R (April 2012). "Antimicrobial properties of amyloid peptides". Molecular Pharmaceutics. 9 (4): 708–17. doi:10.1021/mp200419b. PMC 3297685. PMID 22081976.
  19. Schluesener HJ, Su Y, Ebrahimi A, Pouladsaz D (June 2012). "Antimicrobial peptides in the brain: neuropeptides and amyloid". Frontiers in Bioscience. 4 (4): 1375–80. doi:10.2741/S339. PMID 22652879.
  20. Li H, Liu CC, Zheng H, Huang TY (2018). "Amyloid, tau, pathogen infection and antimicrobial protection in Alzheimer's disease -conformist, nonconformist, and realistic prospects for AD pathogenesis". Translational Neurodegeneration. 7: 34. doi:10.1186/s40035-018-0139-3. PMC 6306008. PMID 30603085.
  21. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. (August 2012). "A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β". Science Translational Medicine. 4 (147): 147ra111. doi:10.1126/scitranslmed.3003748. PMC 3551275. PMID 22896675.
  22. Shen Y, Joachimiak A, Rosner MR, Tang WJ (October 2006). "Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism". Nature. 443 (7113): 870–4. Bibcode:2006Natur.443..870S. doi:10.1038/nature05143. PMC 3366509. PMID 17051221.
  23. King JV, Liang WG, Scherpelz KP, Schilling AB, Meredith SC, Tang WJ (July 2014). "Molecular basis of substrate recognition and degradation by human presequence protease". Structure. 22 (7): 996–1007. doi:10.1016/j.str.2014.05.003. PMC 4128088. PMID 24931469.
  24. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, et al. (October 2013). "Sleep drives metabolite clearance from the adult brain". Science. 342 (6156): 373–7. Bibcode:2013Sci...342..373X. doi:10.1126/science.1241224. PMC 3880190. PMID 24136970.
  25. Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, et al. (August 2015). "Clearance systems in the brain-implications for Alzheimer disease". Nature Reviews. Neurology. 11 (8): 457–70. doi:10.1038/nrneurol.2015.119. PMC 4694579. PMID 26195256.
  26. Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J (2014). "Amyloid-beta: a crucial factor in Alzheimer's disease". Medical Principles and Practice. 24 (1): 1–10. doi:10.1159/000369101. PMC 5588216. PMID 25471398.
  27. Parker MH, Reitz AB (2000). "Assembly of β-Amyloid Aggregates at the Molecular Level". Chemtracts-Organic Chemistry. 13 (1): 51–56.
  28. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, et al. (August 2008). "Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory". Nature Medicine. 14 (8): 837–42. doi:10.1038/nm1782. PMC 2772133. PMID 18568035. Lay summary – Fox News.
  29. Prelli F, Castaño E, Glenner GG, Frangione B (August 1988). "Differences between vascular and plaque core amyloid in Alzheimer's disease". Journal of Neurochemistry. 51 (2): 648–51. doi:10.1111/j.1471-4159.1988.tb01087.x. PMID 3292706.
  30. Zhao LN, Long H, Mu Y, Chew LY (2012). "The toxicity of amyloid β oligomers". International Journal of Molecular Sciences. 13 (6): 7303–27. doi:10.3390/ijms13067303. PMC 3397527. PMID 22837695.
  31. Arispe N, Rojas E, Pollard HB (January 1993). "Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum". Proceedings of the National Academy of Sciences of the United States of America. 90 (2): 567–71. Bibcode:1993PNAS...90..567A. doi:10.1073/pnas.90.2.567. PMC 45704. PMID 8380642.
  32. Abramov AY, Canevari L, Duchen MR (December 2004). "Calcium signals induced by amyloid beta peptide and their consequences in neurons and astrocytes in culture". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 8th European Symposium on Calcium. 1742 (1–3): 81–7. doi:10.1016/j.bbamcr.2004.09.006. PMID 15590058.
  33. Ekinci FJ, Linsley MD, Shea TB (March 2000). "Beta-amyloid-induced calcium influx induces apoptosis in culture by oxidative stress rather than tau phosphorylation". Brain Research. Molecular Brain Research. 76 (2): 389–95. doi:10.1016/S0169-328X(00)00025-5. PMID 10762716.
  34. Pannuzzo M, Milardi D, Raudino A, Karttunen M, La Rosa C (June 2013). "Analytical model and multiscale simulations of Aβ peptide aggregation in lipid membranes: towards a unifying description of conformational transitions, oligomerization and membrane damage". Physical Chemistry Chemical Physics. 15 (23): 8940–51. Bibcode:2013PCCP...15.8940P. doi:10.1039/c3cp44539a. PMID 23588697.
  35. Pannuzzo M (June 2016). "On the physiological/pathological link between Aβ peptide, cholesterol, calcium ions and membrane deformation: A molecular dynamics study". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1858 (6): 1380–9. doi:10.1016/j.bbamem.2016.03.018. PMID 27003127.
  36. Ghiso J, Frangione B (December 2002). "Amyloidosis and Alzheimer's disease". Advanced Drug Delivery Reviews. 54 (12): 1539–51. doi:10.1016/S0169-409X(02)00149-7. PMID 12453671.
  37. Selkoe DJ (October 2001). "Clearing the brain's amyloid cobwebs". Neuron. 32 (2): 177–80. doi:10.1016/S0896-6273(01)00475-5. PMID 11683988.
  38. Hardy J, Duff K, Hardy KG, Perez-Tur J, Hutton M (September 1998). "Genetic dissection of Alzheimer's disease and related dementias: amyloid and its relationship to tau". Nature Neuroscience. 1 (5): 355–8. doi:10.1038/1565. PMID 10196523.
  39. Roses AD (February 1998). "Alzheimer diseases: a model of gene mutations and susceptibility polymorphisms for complex psychiatric diseases". American Journal of Medical Genetics. 81 (1): 49–57. doi:10.1002/(SICI)1096-8628(19980207)81:1<49::AID-AJMG10>3.0.CO;2-W. PMID 9514588.
  40. Xie L, Helmerhorst E, Taddei K, Plewright B, Van Bronswijk W, Martins R (May 2002). "Alzheimer's beta-amyloid peptides compete for insulin binding to the insulin receptor". The Journal of Neuroscience. 22 (10): RC221. doi:10.1523/JNEUROSCI.22-10-j0001.2002. PMC 6757630. PMID 12006603.
  41. Ray WJ, Yao M, Mumm J, Schroeter EH, Saftig P, Wolfe M, et al. (December 1999). "Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch". The Journal of Biological Chemistry. 274 (51): 36801–7. doi:10.1074/jbc.274.51.36801. PMID 10593990.
  42. Roberts SB (December 2002). "Gamma-secretase inhibitors and Alzheimer's disease". Advanced Drug Delivery Reviews. 54 (12): 1579–88. doi:10.1016/S0169-409X(02)00155-2. PMID 12453675.
  43. Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, et al. (October 1999). "Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE". Science. 286 (5440): 735–41. doi:10.1126/science.286.5440.735. PMID 10531052.
  44. Vassar R (December 2002). "Beta-secretase (BACE) as a drug target for Alzheimer's disease". Advanced Drug Delivery Reviews. 54 (12): 1589–602. doi:10.1016/S0169-409X(02)00157-6. PMID 12453676.
  45. Zlokovic BV, Frangione B (2003). Transport-clearance hypothesis for Alzheimer's disease and potential therapeutic implications. Landes Bioscience. pp. 114–122.
  46. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (June 1985). "Amyloid plaque core protein in Alzheimer disease and Down syndrome". Proceedings of the National Academy of Sciences of the United States of America. 82 (12): 4245–9. Bibcode:1985PNAS...82.4245M. doi:10.1073/pnas.82.12.4245. PMC 397973. PMID 3159021.
  47. Castaño EM, Prelli F, Soto C, Beavis R, Matsubara E, Shoji M, Frangione B (December 1996). "The length of amyloid-beta in hereditary cerebral hemorrhage with amyloidosis, Dutch type. Implications for the role of amyloid-beta 1-42 in Alzheimer's disease". The Journal of Biological Chemistry. 271 (50): 32185–91. doi:10.1074/jbc.271.50.32185. PMID 8943274.
  48. Roher AE, Lowenson JD, Clarke S, Woods AS, Cotter RJ, Gowing E, Ball MJ (November 1993). "beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease". Proceedings of the National Academy of Sciences of the United States of America. 90 (22): 10836–40. Bibcode:1993PNAS...9010836R. doi:10.1073/pnas.90.22.10836. PMC 47873. PMID 8248178.
  49. Shinkai Y, Yoshimura M, Ito Y, Odaka A, Suzuki N, Yanagisawa K, Ihara Y (September 1995). "Amyloid beta-proteins 1-40 and 1-42(43) in the soluble fraction of extra- and intracranial blood vessels". Annals of Neurology. 38 (3): 421–8. doi:10.1002/ana.410380312. PMID 7668828.
  50. Kamal A, Almenar-Queralt A, LeBlanc JF, Roberts EA, Goldstein LS (December 2001). "Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP". Nature. 414 (6864): 643–8. Bibcode:2001Natur.414..643K. doi:10.1038/414643a. PMID 11740561.
  51. Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, et al. (September 1999). "Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease". The American Journal of Pathology. 155 (3): 853–62. doi:10.1016/S0002-9440(10)65184-X. PMC 1866907. PMID 10487842.
  52. Schirinzi T, Di Lazzaro G, Sancesario GM, Colona VL, Scaricamazza E, Mercuri NB, et al. (December 2017). "Levels of amyloid-beta-42 and CSF pressure are directly related in patients with Alzheimer's disease". Journal of Neural Transmission. 124 (12): 1621–1625. doi:10.1007/s00702-017-1786-8. PMID 28866757.
  53. Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG (April 2003). "Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis". Science. 300 (5618): 486–9. Bibcode:2003Sci...300..486K. doi:10.1126/science.1079469. PMID 12702875. S2CID 29614957.
  54. Gandy S, Simon AJ, Steele JW, Lublin AL, Lah JJ, Walker LC, et al. (August 2010). "Days to criterion as an indicator of toxicity associated with human Alzheimer amyloid-beta oligomers". Annals of Neurology. 68 (2): 220–30. doi:10.1002/ana.22052. PMC 3094694. PMID 20641005. Lay summary – Drug Discovery and Development.
  55. Jin WS, Bu XL, Liu YH, Shen LL, Zhuang ZQ, Jiao SS, et al. (February 2017). "Plasma Amyloid-Beta Levels in Patients with Different Types of Cancer". Neurotoxicity Research. 31 (2): 283–288. doi:10.1007/s12640-016-9682-9. PMID 27913965.
  56. Lim S, Yoo BK, Kim HS, Gilmore HL, Lee Y, Lee HP, et al. (December 2014). "Amyloid-β precursor protein promotes cell proliferation and motility of advanced breast cancer". BMC Cancer. 14: 928. doi:10.1186/1471-2407-14-928. PMC 4295427. PMID 25491510.
  57. Hartley SL, Handen BL, Devenny D, Mihaila I, Hardison R, Lao PJ, et al. (October 2017). "Cognitive decline and brain amyloid-β accumulation across 3 years in adults with Down syndrome". Neurobiology of Aging. 58: 68–76. doi:10.1016/j.neurobiolaging.2017.05.019. PMC 5581712. PMID 28715661.
  58. Olsson F, Schmidt S, Althoff V, Munter LM, Jin S, Rosqvist S, et al. (January 2014). "Characterization of intermediate steps in amyloid beta (Aβ) production under near-native conditions". The Journal of Biological Chemistry. 289 (3): 1540–50. doi:10.1074/jbc.M113.498246. PMC 3894335. PMID 24225948.
  59. Hartmann T, Bieger SC, Brühl B, Tienari PJ, Ida N, Allsop D, et al. (September 1997). "Distinct sites of intracellular production for Alzheimer's disease A beta40/42 amyloid peptides". Nature Medicine. 3 (9): 1016–20. doi:10.1038/nm0997-1016. PMID 9288729.
  60. Alzheimer's Association (March 2008). "2008 Alzheimer's disease facts and figures". Alzheimer's & Dementia. 4 (2): 110–33. doi:10.1016/j.jalz.2008.02.005. PMID 18631956.
  61. Glenner GG, Wong CW (August 1984). "Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein". Biochemical and Biophysical Research Communications. 122 (3): 1131–5. doi:10.1016/0006-291X(84)91209-9. PMID 6236805.
  62. Zhang S, Iwata K, Lachenmann MJ, Peng JW, Li S, Stimson ER, et al. (June 2000). "The Alzheimer's peptide a beta adopts a collapsed coil structure in water". Journal of Structural Biology. 130 (2–3): 130–41. doi:10.1006/jsbi.2000.4288. PMID 10940221.
  63. Yang M, Teplow DB (December 2008). "Amyloid beta-protein monomer folding: free-energy surfaces reveal alloform-specific differences". Journal of Molecular Biology. 384 (2): 450–64. doi:10.1016/j.jmb.2008.09.039. PMC 2673916. PMID 18835397.
  64. Sgourakis NG, Merced-Serrano M, Boutsidis C, Drineas P, Du Z, Wang C, Garcia AE (January 2011). "Atomic-level characterization of the ensemble of the Aβ(1-42) monomer in water using unbiased molecular dynamics simulations and spectral algorithms". Journal of Molecular Biology. 405 (2): 570–83. doi:10.1016/j.jmb.2010.10.015. PMC 3060569. PMID 21056574.
  65. Sgourakis NG, Yan Y, McCallum SA, Wang C, Garcia AE (May 2007). "The Alzheimer's peptides Abeta40 and 42 adopt distinct conformations in water: a combined MD / NMR study". Journal of Molecular Biology. 368 (5): 1448–57. doi:10.1016/j.jmb.2007.02.093. PMC 1978067. PMID 17397862.
  66. Ahmed M, Davis J, Aucoin D, Sato T, Ahuja S, Aimoto S, et al. (May 2010). "Structural conversion of neurotoxic amyloid-beta(1-42) oligomers to fibrils". Nature Structural & Molecular Biology. 17 (5): 561–7. doi:10.1038/nsmb.1799. PMC 2922021. PMID 20383142.
  67. Yu L, Edalji R, Harlan JE, Holzman TF, Lopez AP, Labkovsky B, et al. (March 2009). "Structural characterization of a soluble amyloid beta-peptide oligomer". Biochemistry. 48 (9): 1870–7. doi:10.1021/bi802046n. PMID 19216516.
  68. Strodel B, Lee JW, Whittleston CS, Wales DJ (September 2010). "Transmembrane structures for Alzheimer's Aβ(1-42) oligomers". Journal of the American Chemical Society. 132 (38): 13300–12. doi:10.1021/ja103725c. PMID 20822103.
  69. Mattson MP (August 2004). "Pathways towards and away from Alzheimer's disease". Nature. 430 (7000): 631–9. Bibcode:2004Natur.430..631M. doi:10.1038/nature02621. PMC 3091392. PMID 15295589.
  70. Flagmeier P, De S, Wirthensohn DC, Lee SF, Vincke C, Muyldermans S, et al. (June 2017). "2+ Influx into Lipid Vesicles Induced by Protein Aggregates". Angewandte Chemie. 56 (27): 7750–7754. doi:10.1002/anie.201700966. PMC 5615231. PMID 28474754.
  71. Citron M (September 2004). "Strategies for disease modification in Alzheimer's disease". Nature Reviews. Neuroscience. 5 (9): 677–85. doi:10.1038/nrn1495. PMID 15322526.
  72. Cummings J, Lee G, Mortsdorf T, Ritter A, Zhong K (September 2017). "Alzheimer's disease drug development pipeline: 2017". review. Alzheimer's & Dementia. 3 (3): 367–384. doi:10.1016/j.trci.2017.05.002. PMC 5651419. PMID 29067343.
  73. Schilling S, Rahfeld JU, Lues I, Lemere CA (May 2018). "Passive Aβ Immunotherapy: Current Achievements and Future Perspectives". review. Molecules. 23 (5): 1068. doi:10.3390/molecules23051068. PMC 6099643. PMID 29751505.
  74. Wang Y, Yan T, Lu H, Yin W, Lin B, Fan W, et al. (2017). "Lessons from Anti-Amyloid-β Immunotherapies in Alzheimer Disease: Aiming at a Moving Target". review. Neuro-Degenerative Diseases. 17 (6): 242–250. doi:10.1159/000478741. PMID 28787714.
  75. Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A, Teichberg S, Callaway DJ (November 2002). "New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease". The Journal of Biological Chemistry. 277 (45): 42881–90. doi:10.1074/jbc.M206593200. PMID 12167652.
  76. Sharma S, Nehru B, Saini A (September 2017). "Inhibition of Alzheimer's amyloid-beta aggregation in-vitro by carbenoxolone: Insight into mechanism of action". primary. Neurochemistry International. 108: 481–493. doi:10.1016/j.neuint.2017.06.011. PMID 28652220.
  77. Parker MH, Chen R, Conway KA, Lee DH, Luo C, Boyd RE, et al. (November 2002). "Synthesis of (-)-5,8-dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydronaphthalene: an inhibitor of beta-amyloid(1-42) aggregation". Bioorganic & Medicinal Chemistry. 10 (11): 3565–9. doi:10.1016/S0968-0896(02)00251-1. PMID 12213471.
  78. Finder VH, Vodopivec I, Nitsch RM, Glockshuber R (February 2010). "The recombinant amyloid-beta peptide Abeta1-42 aggregates faster and is more neurotoxic than synthetic Abeta1-42". Journal of Molecular Biology. 396 (1): 9–18. doi:10.1016/j.jmb.2009.12.016. PMID 20026079.
  79. "State of aggregation". Nature Neuroscience. 14 (4): 399. April 2011. doi:10.1038/nn0411-399. PMID 21445061.
  80. Refolo LM, Pappolla MA, LaFrancois J, Malester B, Schmidt SD, Thomas-Bryant T, et al. (October 2001). "A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease". Neurobiology of Disease. 8 (5): 890–9. doi:10.1006/nbdi.2001.0422. PMID 11592856.
  81. Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY (May 2002). "Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice". Proceedings of the National Academy of Sciences of the United States of America. 99 (11): 7705–10. Bibcode:2002PNAS...99.7705L. doi:10.1073/pnas.092034699. PMC 124328. PMID 12032347.
  82. Schneider JS, Pioli EY, Jianzhong Y, Li Q, Bezard E (April 2013). "Effects of memantine and galantamine on cognitive performance in aged rhesus macaques". Neurobiology of Aging. 34 (4): 1126–32. doi:10.1016/j.neurobiolaging.2012.10.020. PMID 23158762.
  83. Polis B, Srikanth KD, Elliott E, Gil-Henn H, Samson AO (October 2018). "L-Norvaline Reverses Cognitive Decline and Synaptic Loss in a Murine Model of Alzheimer's Disease". Neurotherapeutics. 15 (4): 1036–1054. doi:10.1007/s13311-018-0669-5. PMC 6277292. PMID 30288668.
  84. Heurling K, Leuzy A, Zimmer ER, Lubberink M, Nordberg A (February 2016). "Imaging β-amyloid using [(18)F]flutemetamol positron emission tomography: from dosimetry to clinical diagnosis". European Journal of Nuclear Medicine and Molecular Imaging. 43 (2): 362–373. doi:10.1007/s00259-015-3208-1. PMID 26440450.
  85. Ito H, Shimada H, Shinotoh H, Takano H, Sasaki T, Nogami T, et al. (June 2014). "Quantitative Analysis of Amyloid Deposition in Alzheimer Disease Using PET and the Radiotracer ¹¹C-AZD2184". Journal of Nuclear Medicine. 55 (6): 932–8. doi:10.2967/jnumed.113.133793. PMID 24732152.
  86. Schmidt SD, Nixon RA, Mathews PM (2012). Tissue processing prior to analysis of Alzheimer's disease associated proteins and metabolites, including Aβ. Methods in Molecular Biology. 849. pp. 493–506. doi:10.1007/978-1-61779-551-0_33. ISBN 978-1-61779-550-3. PMID 22528111.
  87. Schmidt SD, Mazzella MJ, Nixon RA, Mathews PM (2012). "Aβ measurement by enzyme-linked immunosorbent assay". Amyloid Proteins. Methods in Molecular Biology. 849. pp. 507–27. doi:10.1007/978-1-61779-551-0_34. ISBN 978-1-61779-550-3. PMID 22528112.
  88. Stine WB, Dahlgren KN, Krafft GA, LaDu MJ (March 2003). "In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis". The Journal of Biological Chemistry. 278 (13): 11612–22. doi:10.1074/jbc.M210207200. PMID 12499373.
  89. Gengler S, Gault VA, Harriott P, Hölscher C (June 2007). "Impairments of hippocampal synaptic plasticity induced by aggregated beta-amyloid (25-35) are dependent on stimulation-protocol and genetic background". Experimental Brain Research. 179 (4): 621–30. doi:10.1007/s00221-006-0819-6. PMID 17171334.
  90. Rekas A, Jankova L, Thorn DC, Cappai R, Carver JA (December 2007). "Monitoring the prevention of amyloid fibril formation by alpha-crystallin. Temperature dependence and the nature of the aggregating species". The FEBS Journal. 274 (24): 6290–304. doi:10.1111/j.1742-4658.2007.06144.x. PMID 18005258.
  91. Sanghera N, Swann MJ, Ronan G, Pinheiro TJ (October 2009). "Insight into early events in the aggregation of the prion protein on lipid membranes". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1788 (10): 2245–51. doi:10.1016/j.bbamem.2009.08.005. PMID 19703409.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.