Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation. |
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| Authors: | F G Gervais D Xu G S Robertson J P Vaillancourt Y Zhu J Huang A LeBlanc D Smith M Rigby M S Shearman E E Clarke H Zheng L H Van Der Ploeg S C Ruffolo N A Thornberry S Xanthoudakis R J Zamboni S Roy D W Nicholson |
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| Institution: | Department of Pharmacology, Biochemistry, and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Merck Research Laboratories, Kirkland, Quebec, Canada. |
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| Abstract: | 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. |
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