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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 (Aβ or Abeta) is a peptide of 39–43 amino acids that appear to be the main constituent of amyloid plaques in the brains of Alzheimer's disease patients. Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis, a muscle disease. Aβ also forms aggregates coating cerebral blood vessels in cerebral amyloid angiopathy. These plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibers,[1] a protein fold shared by other peptides such as prions associated with protein misfolding diseases. Research on laboratory rats suggest that the two-molecule, soluble form of the peptide is a causative agent in the development of Alzheimer's and that the two-molecule form is the smallest synaptotoxic species of soluble amyloid beta oligomer. [2][3]

Contents

Formation

Aβ is formed after sequential cleavage of the amyloid precursor protein, a transmembrane glycoprotein of undetermined function. APP can be processed by α-, β- and γ-secretases; 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 39-43 amino acid residues in length. The most common isoforms are Aβ40 and Aβ42; the shorter form is typically produced by cleavage that occurs in the endoplasmic reticulum, while the longer form is produced by cleavage in the trans-Golgi network.[4] 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.[5]

Genetics

Autosomal-dominant mutations in APP cause hereditary early-onset Alzheimer's disease, likely as a result of altered proteolytic processing. 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)[6] 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. Intra-cellular deposits of tau protein are also seen in the disease, and may also be implicated. The oligomers that form on the amyloid pathway, rather than the mature fibrils, may be the cytotoxic species.[7]

Intervention strategies

Researchers in Alzheimer's disease have identified five strategies as possible interventions against amyloid:[8]

  • 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.
  • Immunotherapies. These stimulate the host immune system to recognize and attack Aβ or provide antibodies that either prevent plaque deposition or enhance clearance of plaques.
  • Anti-aggregation agents[9]such as apomorphine. These prevent Aβ fragments from aggregating or clear aggregates once they are formed.[10]

There is some indication that supplementation of the hormone melatonin may be effective against amyloid.[11][12] 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).[13]

Circadian rhythm of amyloid beta

A 2009 report has just shown that amyloid beta production follows a circadian rhythm, rising when an animal (mice) or person is awake and falling during sleep.[13] The wakefulness-promoting neuroprotein orexin was shown to be necessary for the circadian rhythm of amyloid beta production.[13] 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.[13] 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.[14] This "sundowning" phenomenon could be directly or indirectly related to the recently discovered continuous increase in amyloid beta throughout the day.

Measuring amyloid beta

There are many different ways to measure Amyloid beta. One highly sensitive method is ELISA which is an immunosorbent assay which utilizes a pair of antibodies that recognize Amyloid beta.

Imaging compounds, notable Pittsburgh Compound-B, (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.[15]

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.[16][17] These aggregate processes can also be studied on lipid bilayer constructs.[18]

External links

References

  1. ^ Michael H. Parker; Reitz, Allen B (2000). "Assembly of β-Amyloid Aggregates at the Molecular Level". Chemtracts-Organic Chemistry 13 (1): 51-56. 
  2. ^ Scmid, Randolf (June 2008). "New clue to Alzheimer's found" ( – Scholar search). Yahoo News. http://news.yahoo.com/s/ap/20080622/ap_on_sc/sci_alzheimer_s_clue. 
  3. ^ Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008). "Amyloid-protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory". Nature Medicine 14 (June 22, 2008 online): 837. doi:10.1038/nm1782. PMID 18568035. 
  4. ^ Hartmann T, Bieger SC, Brühl B, et al. (1997). "Distinct sites of intracellular production for Alzheimer's disease Aβ40/42 amyloid peptides". Nat. Med. 3 (9): 1016–20. doi:10.1038/nm0997-1016. PMID 9288729. 
  5. ^ Yin YI, Bassit B, Zhu L, Yang X, Wang C, Li YM (2007). "γ-Secretase Substrate Concentration Modulates the Aβ42/Aβ40 Ratio: Implications for Alzheimer's disease". J. Biol. Chem. 282 (32): 23639–44. doi:10.1074/jbc.M704601200. PMID 17556361. 
  6. ^ Lue LF, Kuo YM, Roher AE, et al. (1999). "Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease". Am. J. Pathol. 155 (3): 853–62. PMID 10487842. PMC 1866907. http://ajp.amjpathol.org/cgi/pmidlookup?view=long&pmid=10487842. 
  7. ^ Kayed R, Head E, Thompson JL, et al. (2003). "Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis". Science (journal) 300 (5618): 486–9. doi:10.1126/science.1079469. PMID 12702875. 
  8. ^ Citron M (2004). "Strategies for disease modification in Alzheimer's disease". Nat. Rev. Neurosci. 5 (9): 677–85. doi:10.1038/nrn1495. PMID 15322526. 
  9. ^ Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A, Teichberg S, Callaway DJE (2002). "New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease". J Biol Chem 277 (45): 42881–42890. doi:10.1074/jbc.M206593200. PMID 12167652. http://www.jbc.org/cgi/content/abstract/277/45/42881. 
  10. ^ Michael H. Parker, Robert Chen, Kelly A. Conway, Daniel H. S. Lee; Chi Luoi, Robert E. Boyd, Samuel O. Nortey, Tina M. Ross, Malcolm K. Scott, Allen B. Reitz (2002). "Synthesis of (+)-5,8-Dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydro-naphthalene: An Inhibitor of β-Amyloid1-42 Aggregation". Bioorg. Med. Chem 10 (11): 3565–3569. doi:10.1016/S0968-0896(02)00251-1. PMID 12213471. 
  11. ^ Lahiri DK, Chen DM, Lahiri P, Bondy S, Greig NH (November 2005). "Amyloid, cholinesterase, melatonin, and metals and their roles in aging and neurodegenerative diseases". Ann. N. Y. Acad. Sci. 1056: 430–49. doi:10.1196/annals.1352.008. PMID 16387707. http://www.annalsnyas.org/cgi/pmidlookup?view=long&pmid=16387707. 
  12. ^ Wang XC, Zhang YC, Chatterjie N, Grundke-Iqbal I, Iqbal K, Wang JZ (June 2008). "Effect of melatonin and Melatonylvalpromide on beta-amyloid and neurofilaments in N2a cells". Neurochem. Res. 33 (6): 1138–44. doi:10.1007/s11064-007-9563-y. PMID 18231852. 
  13. ^ a b c d J. E. Kang, M. M. Lim, R. J. Bateman, J. J. Lee, L. P. Smyth, J. R. Cirrito, N. Fujiki, S. Nishino and D. M. Holtzman (2009). "Amyloid-{beta} Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle". Science. doi:10.1126/science.1180962. 
  14. ^ Volicer L, Harper D, Manning B, Goldstein R, Satlin A (2001). "Sundowning and circadian rhythms in Alzheimer's disease". Am J Psychiatry 158 (5): 704–11. doi:10.1176/appi.ajp.158.5.704. PMID 11329390. 
  15. ^ Stine WB, Dahlgren KN, Krafft GA, LaDu MJ (March 2003). "In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis". J. Biol. Chem. 278 (13): 11612–22. doi:10.1074/jbc.M210207200. PMID 12499373. 
  16. ^ S Gengler, VA Gault, P Harriott and C Hölscher Impairments of hippocampal synaptic plasticity induced by aggregated beta-amyloid (25-35) are dependent on stimulation-protocol and genetic background. Experimental Brain Research Volume 179, Number 4, June 2007 , pp. 621-630(10) (2006)
  17. ^ Rekas A, Jankova L, Thorn DC, Cappai R, Carver JA Monitoring the prevention of amyloid fibril formation by alpha-crystallin. Temperature dependence and the nature of the aggregating species. FEBS J. (2007) 274(24), 6290-304
  18. ^ Narinder Sanghera, Marcus J. Swann, Gerry Ronan, Teresa J.T. Pinheiro, Insight into early events in the aggregation of the prion protein on lipid membranes, Biochimica et Biophysica Acta (BBA) - Biomembranes, In Press, Corrected Proof, Available online 21 August 2009
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