Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-β precursor protein and amyloidogenic Aβ peptide formation

被引:734
|
作者
Gervais, FG
Xu, DG
Robertson, GS
Vaillancourt, JP
Zhu, YX
Huang, JQ
LeBlanc, A
Smith, D
Rigby, M
Shearman, MS
Clarke, FE
Zheng, H
Van Der Ploeg, LHT
Ruffolo, SC
Thornberry, NA
Xanthoudakis, S
Zamboni, RJ
Roy, S
Nicholson, DW [1 ]
机构
[1] Merck Res Labs, Merck Frosst Ctr Therapeut Res, Dept Pharmacol Biochem & Mol Biol, Kirkland, PQ H9H 3L1, Canada
[2] Merck Res Labs, Merck Frosst Ctr Therapeut Res, Dept Med Chem, Kirkland, PQ H9H 3L1, Canada
[3] Merck Sharp & Dohme Res Labs, Neurosci Res Ctr, Dept Pharmacol Biochem & Mol Biol, Harlow CM20 2QR, Essex, England
[4] Merck Res Labs, Dept Enzymol, Rahway, NJ 07065 USA
[5] Merck Res Labs, Dept Metab Disorders, Rahway, NJ 07065 USA
[6] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada
[7] Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
关键词
D O I
10.1016/S0092-8674(00)80748-5
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The amyloid-beta precursor protein (APP) is directly and efficiently cleaved by caspases during apoptosis, resulting in elevated amyloid-beta (A beta) peptide formation. The predominant site of caspase-mediated proteolysis is within the cytoplasmic tail of APP, and cleavage at this site occurs in hippocampal neurons in vivo following acute excitotoxic or ischemic brain injury. Caspase-3 is the predominant caspase involved in APP cleavage, consistent with its marked elevation in dying neurons of Alzheimer's disease brains and colocalization of its APP cleavage product with A beta in senile plaques. Caspases thus appear to play a dual role in proteolytic processing of APP and the resulting propensity for A beta peptide formation, as well as in the ultimate apoptotic death of neurons in Alzheimer's disease.
引用
收藏
页码:395 / 406
页数:12
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