Amyloid-β proteins (Aβ) of 42 (Aβ42) and 40 aa (Aβ40) accumulate as senile plaques (SP) and
cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer’s disease (AD).
A number of rare mutations linked to familial AD (FAD) on the Aβ precursor protein (APP), Presenilin-1 (PS1), Presenilin-
2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E
(ApoE-ε4) foster the accumulation of Aβ and also induce the entire spectrum of pathology associated with the disease. Aβ
accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially
processed by β-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral
membrane protease, to generate Aβ. Although Aβ accumulates in all forms of AD, the only pathways known to be affected
in FAD increase Aβ production by APP gene duplication or via base substitutions on APP and γ-secretase subunits
PS1 and PS2 that either specifically increase the yield of the longer Aβ42 or both Aβ40 and Aβ42. However, the vast majority
of AD patients accumulate Aβ without these known mutations. This led to proposals that impairment of Aβ degradation
or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme
(IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin,
and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal
models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of
Aβ and we have recently established that the mechanism is by skirting Aβ degradation. This review outlines major cellular
pathways of Aβ degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible
for Aβ turnover.
Keywords: Alzheimer’s disease, amyloid β degradation, amyloid β peptide, endothelin-converting enzyme, insulin-degrading
enzyme, neprilysin, neurodegeneration.
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