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A4 amyloid peptide; beta-peptide

A4 is formed from a larger precursor molecule, the amyloid precursor protein (APP). A4 was originally isolated from amyloid-laden meningeal arterioles & venules in patients with Alzheimer's disease or Down's syndrome. [10] Function: Formation of A4: 1) coordinate activity of beta- & gamma-secretases result in formation of A4 (see membrane region of APP) 2) ADOLS may be intermediates in formation of amyloid plaques 3) regulation by cholesterol & cholesterol esters a) formation of A4 in cultured neurons is increased by addition of cholesterol to the medium [9] b) rabbits fed cholesterol accumulate A4 in brain [13] c) statins diminish A4 & A4/42 production by neurons in culture d) lovastatin reduces A4 in plasma of human patients e) statins diminish beta- & gamma-secretase activity in cultured cells [9] f) statins increase alpha-secretase activity in cultured cells [9] g) A4 production in cultured cells depends on cholesterol ester levels not on total cholesterol [9] h) inhibition of acyl-cholesterol acyltransferase (ACAT) diminishes A4 production [9] 4) in animal models, some NSAIDs diminished A4/42 production a) NSAIDS that diminished A4/42 production [6] - flurbiprofen, ibuprofen, indomethacin, sulindac b) NSAIDS that did NOT diminish A4/42 production - aspirin, naproxen, celecoxib 5) increased sumoylation of APP with poly(SUMO3)chains is associated with diminished A4-amyloid peptide production [15] 6) amyloid beta peptide (Abeta) accumulates in brain rapidly after traumatic brain injury [35] - Abeta is released during a stress response [37] * NSAIDs = non-steroidal anti-inflammatory drugs Degradation of A4:* 1) proteases that degrade A4 include: [5] a) insulinase (insulin-degrading enzyme) b) neprilysin (CD10) c) plasmin d) endothelin converting enzyme 1 e) matrix metalloproteinase 9 f) tissue plasminogen activator g) urokinase h) PITRM1 (mitochondrial) 2) inhibitors of ACAT1 enhance beta peptide & amyloid plaque removal in a mouse model for Alzheimer's disease [27] 3) LRP1 on brain capillaries clears A4 from brain 4) other implicated proteins: COLEC12 * alpha-2 macroglobulin may participate in clearance & degradation of A4 [12] Interaction of A4 with other proteins: 1) charged residues in the 1-11 region of A4 activate the contact system [7] 2) same region binds to complement C1q 3) excessive A4 may inhibit lysosomal degradation of proteins [16] 4) RAGE receptor binds A4 5) prion protein PrPc (CD230) may bind & internalize A4 oligomers [34] 6) COL25A1 high affinity for Cu+2, Fe+3 & Zn+2 in vitro [14] A4 as antioxidant: - Met-35 reversibly oxidizes to sulfoxide, thus A4 may function as antioxidant [23] Kinetic parameters: - 1/2 life of A4 in CSF is about 6-7 hours [29] Structure: - polypeptides of 37-42 amino acids. - A4/40 is the majority species - A4/37-39 & A4/42 are minority species [1] - A4 forms amyloid peptide oligomers Compartment: - soluble A4 is within endosomes, trans-GOLGI & endoplasmic reticulum (ER) [8] - in neurons, A4/42 is generated in the endoplasmic reticulum, & A4/40 from the trans-Golgi network [2] - some A4 appears to be generated in recycling endosomes after clathrin-mediated endocytosis of surface APP - A4 (A4/40 > A4/42) is a normal constituent of cerebrospinal fluid (3-8 nM) & plasma (< 0.5 nM) [10]; A4/42 may be presentin amounts too low to detect [25] Expression: - soluble A4 is produced as part of normal APP metabolism - virtually all peripheral cells express APP & generate A4 [10] Pathology: A4 is found in: 1) senile plaques 2) cerebrovascular amyloid angiopathy 3) neurofibrillary tangles & neuropil threads associated with: - aging, Alzheimer's disease & older Down's syndrome patients 4) Nonaka distal myopathy 5) inclusion body myopathy 2 [30.31] 6) within astrocytes & neurons (pyramidal cells) in AD [30,31] 7) posterior cortical atrophy Deposition of A4: 1) A4 binds to apo E & the E4 allele may enhance A4 deposition 2) oligomers or polymers (fibrils) of A4/42 in lipoprotein complexes associated with GM1 may be the initial precipitating species [11] 3) A4/40 does not readily for oligomers [26] 4) A4 binding of acetylcholinesterase which may enhance amyloid plaque formation [22] 5) may occur after lysis of neurons &/or astrocytes containing A4/42 [30,31] Toxicity of A4: 1) may be enhanced by cholinergic depletion [17] 2) A4 disrupts acetylcholine synthesis [17] 3) A4 disrupts muscarinic signal transduction [17] 4) nicotinic receptor alpha-7 transmission may be protective [17] a) exposure to beta-amyloid results in the activation of caspase-3 & cleavage of the DNA-repair enzyme poly-[ADP-ribose] polymerase b) nicotine inhibits these effects through JAK2 activation [18-20] 5) other nicotinic receptors may also diminish A4 toxicity [21] 6) resveratrol may inhibit A4 toxicity through induction of protein kinase C [24] 7) SH3PXD2A may mediate neurotoxic effect of A4 in association with ADAM12 (see SH3PXD2A) 8) soluble A4 impairs long-term potentiation (LTP) & long-term depression (LTD) [33] 9) in a study of a mouse model for AD, it is proposed that Abeta may exert on the CRF receptor resulting in damage to the hippocampus resulting from increased corticosteroid release in response to minor stress [37] Laboratory: - lower plasma A-beta 42/40 was associated with greater cognitive decline over a 9-year period [36] Notes: All forms of A4 are found, to some extent, in senile plaques; however, A4/42 is considered the major pathologic form. [10] A4/42 is far more prone to aggregate into fibrils than A4/40. A4/42 is detected earlier in diffuse plaques; A4/40 is detected later. A4/42 is the main component of amyloid deposits in AD. A4/40 is found is small arterioles, venules & capillaries with cerebral cortex also bearing amyloid plaques (see cerebral amyloid angiopathy).

Interactions

molecular events

Related

Alzheimer's disease (AD) amyloid precursor protein (APP) or A4/beta amyloid precursor protein amyloid-beta peptide in body fluid cerebral amyloid angiopathy (CAA) collagen 25 alpha-1; CLAC-P; Alzheimer disease amyloid-associated protein; AMY; contains: collagen-like Alzheimer amyloid plaque component (CLAC) (COL25A1) complement C1q contact system degradation of A4 formation of A4 GM1 ganglioside; monosialoganglioside posterior cortical atrophy

Specific

Alzheimer's disease A4 peptide oligomer (A-beta oligomer, A-beta derived diffusable ligand, ADDL)

General

amyloid oligomerizing protein secreted peptide

Figures/Diagrams

Figures/diagrams/slides/tables related to A4 amyloid peptide

Properties

SIZE: entity length = 40 aa entity length = 42 aa COMPARTMENT: extracellular compartment

References

  1. Goedert M, Strittmatter WJ, Roses AD. Alzheimer's disease. Risky apolipoprotein in brain. Nature. 1994 Nov 3;372(6501):45-6. No abstract available. PMID: 7969418 {A4 size}
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  3. Selkoe DJ. Translating cell biology into therapeutic advances in Alzheimer's disease. Nature. 1999 Jun 24;399(6738 Suppl):A23-31. Review. PMID: 10392577
  4. Journal Watch 20(5):38, 2000 Iwata N, Tsubuki S, Takaki Y, Watanabe K, Sekiguchi M, Hosoki E, Kawashima-Morishima M, Lee HJ, Hama E, Sekine-Aizawa Y, Saido TC. Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med. 2000 Feb;6(2):143-50. PMID: 10655101
  5. Selkoe DJ. Clearing the brain's amyloid cobwebs. Neuron. 2001 Oct 25;32(2):177-80. Review. PMID: 11683988
  6. Journal Watch 21(24):194, 2001 Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, Smith TE, Murphy MP, Bulter T, Kang DE, Marquez-Sterling N, Golde TE, Koo EH. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001 Nov 8;414(6860):212-6. PMID: 11700559
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  8. Kamal A, Almenar-Queralt A, LeBlanc JF, Roberts EA, Goldstein LS. Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature. 2001 Dec 6;414(6864):643-8. PMID: 11740561
  9. Marx J. Science 294:509, 2001
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  12. Maccioni RB et al The molecular bases of Alzheimer's disease and other neurodegenerative disorders. Arch Med Res. 2001 Sep-Oct;32(5):367-81. Review. PMID: 11578751
  13. Hartmann T. Cholesterol, A beta and Alzheimer's disease. Trends Neurosci. 2001 Nov;24(11 Suppl):S45-8. Review. PMID: 11881745
  14. Melov S. '...and C is for Clioquinol' - the AbetaCs of Alzheimer's disease. Trends Neurosci. 2002 Mar;25(3):121-3; discussion 123-4. Review. PMID: 11852134
  15. Li Y, Wang H, Wang S, Quon D, Liu YW, Cordell B. Positive and negative regulation of APP amyloidogenesis by sumoylation. Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):259-64. Epub 2002 Dec 27. Erratum in: Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):9102. PMID: 12506199
  16. Hu W, Gray NW, Brimijoin S. Amyloid-beta increases acetylcholinesterase expression in neuroblastoma cells by reducing enzyme degradation. J Neurochem. Jul;86(2):470-8. 2003 PMID: 12871588
  17. Mesulam M. The cholinergic lesion of Alzheimer's disease: pivotal factor or side show? Learn Mem. 2004 Jan-Feb;11(1):43-9. Review. PMID: 14747516
  18. Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Shibasaki H, Kume T, Akaike A. alpha 7 nicotinic receptor transduces signals to phosphatidyl-inositol 3-kinase to block A beta-amyloid- induced neurotoxicity. J Biol Chem. 2001 Apr 27;276(17):13541-6. Epub 2001 Jan 19. PMID: 11278378
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  20. Shaw S, Bencherif M, Marrero MB. Janus kinase 2, an early target of alpha 7 nicotinic acetylcholine receptor-mediated neuroprotection against Abeta-(1-42) amyloid. J Biol Chem. 2002 Nov 22;277(47):44920-4. Epub 2002 Sep 18. PMID: 12244045
  21. Kihara T, Shimohama S, Urushitani M, Sawada H, Kimura J, Kume T, Maeda T, Akaike A. Stimulation of alpha4beta2 nicotinic acetylcholine receptors inhibits beta-amyloid toxicity. Brain Res. 1998 May 11;792(2):331-4. PMID: 9593977
  22. Rees T, Hammond PI, Soreq H, Younkin S, Brimijoin S. Acetylcholinesterase promotes beta-amyloid plaques in cerebral cortex. Neurobiol Aging. Oct;24(6):777-87. 2003 PMID: 12927760
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  25. http://www.medscape.com/viewarticle/477715
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  28. Society for Neursociences (SFN) 2004 Annual Meeting
  29. Bateman, Randall. Assistant Professor of Neurology, Washington University Medical School, reported in Netscape Nov 18, 2006 Nature Nov 2006
  30. Nagele RG, D'Andrea MR, Lee H, Venkataraman V, Wang HY. Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res. 2003 May 9;971(2):197-209. PMID: 12706236
  31. D'Andrea MR, Nagele RG, Wang HY, Lee DH. Consistent immunohistochemical detection of intracellular beta-amyloid42 in pyramidal neurons of Alzheimer's disease entorhinal cortex. Neurosci Lett. 2002 Nov 29;333(3):163-6. PMID: 1242937
  32. Sagare A et al, Clearance of amyloid-beta by circulating lipoprotein receptors Nat Med 2007, 13:1029 PMID: 17694066
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  34. Lauren J et al. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-oligomers. Nature 2009 Feb 26; 457:1128 PMID: 19242475 - Cisse M and Mucke L. Alzheimer's disease: A prion protein connection. Nature 2009 Feb 26; 457:1090. PMID: 19242462
  35. Loane DJ et al Amyloid precursor protein secretases as therapeutic targets for traumatic brain injury. Nat Med 2009 Apr; 15:377. PMID: 19287391
  36. Yaffe K et al. Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline. JAMA 2011 Jan 19; 305:261. PMID: 21245181
  37. Justice NJ et al. Posttraumatic stress disorder-like induction elevates beta- amyloid levels, which directly activates corticotropin- releasing factor neurons to exacerbate stress responses. J Neurosci 2015 Feb 11; 35:2612 PMID: 25673853 http://www.jneurosci.org/content/35/6/2612

Component-of

molecular complex