Understanding the Brain

Beta amyloid

From Cognopedia
Jump to: navigation, search
  1. REDIRECT Template:Infobox protein
Beta-amyloid peptide (beta-APP)
PDB 1ba6 EBI.jpg
solution structure of the methionine-oxidized amyloid beta-peptide (1-40). does oxidation affect conformational switching? nmr, 10 structures
Identifiers
Symbol Beta-APP
Pfam PF03494
InterPro IPR013803
SCOP 1ba4

Amyloid beta (Aβ or Abeta) is a peptide of 36–43 amino acids that appears to be the main constituent of amyloid plaques (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,[1] 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.[2]

Formation

Aβ is formed after sequential cleavage of the amyloid precursor protein (APP), 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 36-43 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.[3] 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.[4]

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)[5] 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 KLVFFAAE 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.[6]

An alternative hypothesis is that amyloid oligomers rather than plaques are responsible for the disease. 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.[7]

Structure

Amyloid beta is intrinsically unstructured, meaning that in solution it does not acquire a compact 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. 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.[8] Replica exchange molecular dynamics studies suggested that amyloid beta can indeed populate multiple discrete structural states;[9] more recent studies identified a multiplicity of discrete conformational clusters by statistical analysis.[10] By NMR-guided simulations, amyloid beta 1-40 and amyloid beta 1-42 also seem to feature highly different conformational states,[11] 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.[12] 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;[13] computational studies suggest an antiparallel beta-turn-beta motif instead for membrane-embedded oligomers.[14]

Intervention strategies

Researchers in Alzheimer's disease have identified five strategies as possible interventions against amyloid:[15]

  • 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[16] such as apomorphine. These prevent Aβ fragments from aggregating or clear aggregates once they are formed.[17]

There is some indication that supplementation of the hormone melatonin may be effective against amyloid. Melatonin interacts with amyloid beta and inhibits its agregation [18][19] 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).[20]

The cannabinoid HU-210 has been shown to prevent amyloid beta-promoted inflammation.[21]

Circadian rhythm of amyloid beta

A 2009 report has just shown that amyloid beta production follows a circadian rhythm, rising when an animal (mouse) or person is awake and falling during sleep.[20] The wakefulness-promoting neuroprotein orexin was shown to be necessary for the circadian rhythm of amyloid beta production.[20] 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.[20] This is consistent with recent findings that chronic sleep deprivation is associated with early onset Alzheimer's disease.

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.[22] This "sundowning" phenomenon could be directly or indirectly related to the recently discovered continuous increase in amyloid beta throughout the day.

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.

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.

Imaging compounds, notably 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.[23]

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.[24][25] These aggregate processes can also be studied on lipid bilayer constructs.[26]

Antimicrobial properties

A recent study assessing the antimicrobial properties of amyloid-beta suggests that current theories regarding its role in Alzheimer's disease may be incorrect. In vitro assays demonstrated significant antimicrobial abilities against eight clinically relevant organisms, in several cases exceeding the potency of known antimicrobial peptide LL-37. If amyloid-beta is, in fact, a component of the innate immune system, then Alzheimer's may be an infectious disease caused by a previously unidentified microorganism.[27]

References

  1. Parker MH, Reitz AB (2000). "Assembly of β-Amyloid Aggregates at the Molecular Level". Chemtracts-Organic Chemistry 13 (1): 51–56. 
  2. 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 (August 2008). "Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory". Nat. Med. 14 (8): 837–42. doi:10.1038/nm1782. PMC 2772133. PMID 18568035. Lay summary – Fox News. 
  3. Hartmann T, Bieger SC, Brühl B, Tienari PJ, Ida N, Allsop D, Roberts GW, Masters CL, Dotti CG, Unsicker K, Beyreuther K (September 1997). "Distinct sites of intracellular production for Alzheimer's disease A beta40/42 amyloid peptides". Nat. Med. 3 (9): 1016–20. doi:10.1038/nm0997-1016. PMID 9288729. 
  4. Yin YI, Bassit B, Zhu L, Yang X, Wang C, Li YM (August 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. 
  5. Lue LF, Kuo YM, Roher AE, Brachova L, Shen Y, Sue L, Beach T, Kurth JH, Rydel RE, Rogers J (September 1999). "Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease". Am. J. Pathol. 155 (3): 853–62. PMC 1866907. PMID 10487842. http://ajp.amjpathol.org/cgi/content/full/155/3/853. 
  6. 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. doi:10.1126/science.1079469. PMID 12702875. 
  7. Gandy S, Simon AJ, Steele JW, Lublin AL, Lah JJ, Walker LC, Levey AI, Krafft GA, Levy EF, Checler F, Glabe C, Bilker W, Abel T, Schmeidler J, Ehrlich ME (2010). "Days-to-criterion as an indicator of toxicity associated with human Alzheimer amyloid-beta oligomers". Annals of Neurology 67 (6): n/a. doi:10.1002/ana.22052. PMID 20641005. Lay summary – Drug Discovery and Development. 
  8. doi:10.1006/jsbi.2000.4288
    This citation will be automatically completed in the next few minutes. You can jump the queue or expand by hand
  9. doi:10.1016/j.jmb.2008.09.039
    This citation will be automatically completed in the next few minutes. You can jump the queue or expand by hand
  10. doi:10.1016/j.jmb.2010.10.015
    This citation will be automatically completed in the next few minutes. You can jump the queue or expand by hand
  11. doi:10.1016/j.jmb.2007.02.093
    This citation will be automatically completed in the next few minutes. You can jump the queue or expand by hand
  12. doi:10.1038/nsmb.1799
    This citation will be automatically completed in the next few minutes. You can jump the queue or expand by hand
  13. doi:10.1021/bi802046n
    This citation will be automatically completed in the next few minutes. You can jump the queue or expand by hand
  14. doi:10.1021/ja103725c
    This citation will be automatically completed in the next few minutes. You can jump the queue or expand by hand
  15. Citron M (September 2004). "Strategies for disease modification in Alzheimer's disease". Nat. Rev. Neurosci. 5 (9): 677–85. doi:10.1038/nrn1495. PMID 15322526. 
  16. 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". J. Biol. Chem. 277 (45): 42881–90. doi:10.1074/jbc.M206593200. PMID 12167652. 
  17. 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. 
  18. 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. 
  19. 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. 
  20. 20.0 20.1 20.2 20.3 Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM (November 2009). "Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle". Science 326 (5955): 1005–7. doi:10.1126/science.1180962. PMC 2789838. PMID 19779148. 
  21. doi:10.1523/JNEUROSCI.4540-04.2005
    This citation will be automatically completed in the next few minutes. You can jump the queue or expand by hand
  22. 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. 
  23. 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. 
  24. 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". Exp Brain Res 179 (4): 621–30. doi:10.1007/s00221-006-0819-6. PMID 17171334. 
  25. 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". FEBS J. 274 (24): 6290–304. doi:10.1111/j.1742-4658.2007.06144.x. PMID 18005258. 
  26. Sanghera N, Swann MJ, Ronan G, Pinheiro TJ (October 2009). "Insight into early events in the aggregation of the prion protein on lipid membranes". Biochim. Biophys. Acta 1788 (10): 2245–51. doi:10.1016/j.bbamem.2009.08.005. PMID 19703409. 
  27. Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, Burton MA, Goldstein LE, Duong S, Tanzi RE, Moir RD (2010). "The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide". PLoS ONE 5 (3): e9505. doi:10.1371/journal.pone.0009505. PMC 2831066. PMID 20209079. 

Further reading

  • Martins IC, Kuperstein I, Wilkinson H, Maes E, Vanbrabant M, Jonckheere W, Van Gelder P, Hartmann D, D'Hooge R, De Strooper B, Schymkowitz J, Rousseau F (January 2008). "Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice". EMBO J. 27 (1): 224–33. doi:10.1038/sj.emboj.7601953. PMC 2206134. PMID 18059472. 
</dl>

External links