A4 amyloid peptide; beta-peptide

Introduction

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.

Function

Formation of A4:

• coordinate activity of beta- & gamma-secretases result in formation of A4 (see membrane region of APP)
• ADOLS may be intermediates in formation of amyloid plaques
• regulation by cholesterol & cholesterol esters
  • formation of A4 in cultured neurons is increased by addition of cholesterol to the medium
  • rabbits fed cholesterol accumulate A4 in brain
  • statins diminish A4 & A4/42 production by neurons in culture
  • lovastatin reduces A4 in plasma of human patients
  • statins diminish beta- & gamma-secretase activity in cultured cells
  • statins increase alpha-secretase activity in cultured cells
  • A4 production in cultured cells depends on cholesterol ester levels not on total cholesterol
  • inhibition of acyl-cholesterol acyltransferase (ACAT) diminishes A4 production
• in animal models, some NSAIDs diminished A4/42 production
  • NSAIDS that diminished A4/42 production
    • flurbiprofen, ibuprofen, indomethacin, sulindac
  • NSAIDS that did NOT diminish A4/42 production
    • aspirin, naproxen, celecoxib
• increased sumoylation of APP with poly(SUMO3)chains is associated with diminished A4-amyloid peptide production
• amyloid beta peptide (Abeta) accumulates in brain rapidly after traumatic brain injury
  • Abeta is released during a stress response

* NSAIDs = non-steroidal anti-inflammatory drugs

Degradation of A4:*

• proteases that degrade A4 include:
  • insulinase (insulin-degrading enzyme)
  • neprilysin (CD10)
  • plasmin
  • endothelin converting enzyme 1
  • matrix metalloproteinase 9
  • tissue plasminogen activator
  • urokinase
  • PITRM1 (mitochondrial)
• inhibitors of ACAT1 enhance beta peptide & amyloid plaque removal in a mouse model for Alzheimer's disease
• LRP1 on brain capillaries clears A4 from brain
• other implicated proteins: COLEC12

* alpha-2 macroglobulin may participate in clearance & degradation of A4

Interaction of A4 with other proteins:

• charged residues in the 1-11 region of A4 activate the contact system
• same region binds to complement C1q
• excessive A4 may inhibit lysosomal degradation of proteins
• RAGE receptor binds A4
• prion protein PrPc (CD230) may bind & internalize A4 oligomers
• COL25A1

high affinity for Cu+2, Fe+3 & Zn+2 in vitro

A4 as antioxidant:

• Met-35 reversibly oxidizes to sulfoxide, thus A4 may function as antioxidant

Kinetic parameters:

• 1/2 life of A4 in CSF is about 6-7 hours

Structure

• polypeptides of 37-42 amino acids.
• A4/40 is the majority species
• A4/37-39 & A4/42 are minority species
• A4 forms amyloid peptide oligomers

Compartment

• soluble A4 is within endosomes, trans-GOLGI & endoplasmic reticulum (ER)
• in neurons, A4/42 is generated in the endoplasmic reticulum, & A4/40 from the trans-Golgi network
• 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); A4/42 may be presentin amounts too low to detect

Expression

• soluble A4 is produced as part of normal APP metabolism
• virtually all peripheral cells express APP & generate A4

Pathology

A4 is found in:

• senile plaques
• cerebrovascular amyloid angiopathy
• neurofibrillary tangles & neuropil threads associated with:
  • aging, Alzheimer's disease & older Down's syndrome patients
• Nonaka distal myopathy
• inclusion body myopathy 2 [30.31]
• within astrocytes & neurons (pyramidal cells) in AD
• posterior cortical atrophy

Deposition of A4:

• A4 binds to apo E & the E4 allele may enhance A4 deposition
• oligomers or polymers (fibrils) of A4/42 in lipoprotein complexes associated with GM1 may be the initial precipitating species
• A4/40 does not readily for oligomers
• A4 binding of acetylcholinesterase which may enhance amyloid plaque formation
• may occur after lysis of neurons &/or astrocytes containing A4/42

Toxicity of A4:

• may be enhanced by cholinergic depletion
• A4 disrupts acetylcholine synthesis
• A4 disrupts muscarinic signal transduction
• nicotinic receptor alpha-7 transmission may be protective
  • exposure to beta-amyloid results in the activation of caspase-3 & cleavage of the DNA-repair enzyme poly-[ADP-ribose] polymerase
  • nicotine inhibits these effects through JAK2 activation [18-20]
• other nicotinic receptors may also diminish A4 toxicity
• resveratrol may inhibit A4 toxicity through induction of protein kinase C
• SH3PXD2A may mediate neurotoxic effect of A4 in association with ADAM12 (see SH3PXD2A)
• soluble A4 impairs long-term potentiation (LTP) & long-term depression (LTD)
• 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

Laboratory

• lower plasma A-beta 42/40 was associated with greater cognitive decline over a 9-year period

Notes

All forms of A4 are found, to some extent, in senile plaques; however, A4/42 is considered the major pathologic form. 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).

More general terms

• oligomerizing protein
• secreted peptide
• amyloid

More specific terms

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

Additional terms

• Alzheimer's disease (AD)
• amyloid precursor protein; A4/beta amyloid precursor protein (APP)
• 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

Component of

• amyloid (senile, neuritic) plaque
• Alzheimer's disease A4 peptide oligomer (A-beta oligomer, A-beta derived diffusable ligand, ADDL)