Amyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer's Disease

被引:248
作者
Baranello, Robert J. [1 ]
Bharani, Krishna L. [1 ]
Padmaraju, Vasudevaraju [1 ]
Chopra, Nipun [2 ]
Lahiri, Debomoy K. [2 ]
Greig, Nigel H. [3 ]
Pappolla, Miguel A. [4 ]
Sambamurti, Kumar [1 ]
机构
[1] Med Univ S Carolina, Dept Neurosci, Charleston, SC 29425 USA
[2] Indiana Univ, Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA
[3] NIA, Drug Design & Dev Sect, Intramural Res Program, Baltimore, MD 21224 USA
[4] Univ Texas Med Branch, Dept Neurol, Galveston, TX 77555 USA
关键词
Alzheimer's disease; amyloid beta degradation; amyloid beta peptide; endothelin-converting enzyme; insulin-degrading enzyme; neprilysin; neurodegeneration; INSULIN-DEGRADING ENZYME; ANGIOTENSIN-CONVERTING ENZYME; UBIQUITIN-PROTEASOME PATHWAY; RECEPTOR-RELATED PROTEIN; A-BETA; PRECURSOR PROTEIN; APOLIPOPROTEIN-E; MATRIX METALLOPROTEINASES; GAMMA-SECRETASE; CATHEPSIN-B;
D O I
10.2174/1567205012666141218140953
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Amyloid-beta proteins (A beta) of 42 (A beta 42) and 40 aa (A beta 40) 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 A beta precursor protein (APP), Presenilin-1 (PS1), Presenilin-2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the epsilon 4 allele of Apolipoprotein E (ApoE-epsilon 4) foster the accumulation of A beta and also induce the entire spectrum of pathology associated with the disease. A beta accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by beta-site APP cleaving enzyme (BACE1) and gamma-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate A beta. Although A beta accumulates in all forms of AD, the only pathways known to be affected in FAD increase A beta production by APP gene duplication or via base substitutions on APP and gamma-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer A beta 42 or both A beta 40 and A beta 42. However, the vast majority of AD patients accumulate A beta without these known mutations. This led to proposals that impairment of A beta 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 gamma-secretase inhibitors to paradoxically increase the yield of A beta and we have recently established that the mechanism is by skirting A beta degradation. This review outlines major cellular pathways of A beta degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for A beta turnover.
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页码:32 / 46
页数:15
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