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PMID: 10319819 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation.

Cell ·Vol. 97 ·No. 3 ·1999-04-30 ·Pages 395-406

Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, LeBlanc A, Smith D, Rigby M, Shearman MS, Clarke EE, Zheng H, Van Der Ploeg LH, Ruffolo SC, Thornberry NA, Xanthoudakis S, Zamboni RJ, Roy S, Nicholson DW

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.

MeSH Terms

Acute Disease Alzheimer Disease/enzymology,genetics,pathology Amyloid Precursor Protein Secretases Amyloid beta-Peptides/genetics,metabolism Amyloid beta-Protein Precursor/genetics,metabolism Amyloidosis/enzymology,genetics,pathology Animals Apoptosis/drug effects,genetics Aspartic Acid Aspartic Acid Endopeptidases Brain Diseases/chemically induced,enzymology,pathology Camptothecin/pharmacology Caspase 3 Caspases/analysis,metabolism Cysteine Proteinase Inhibitors/pharmacology Endopeptidases/genetics Enzyme Inhibitors/pharmacology Enzyme Precursors/analysis,metabolism Excitatory Amino Acid Agonists Hippocampus/cytology Humans In Situ Nick-End Labeling Kainic Acid Leukemia, Erythroblastic, Acute Male Mice Mice, Inbred C57BL Mutation/physiology Neurons/chemistry,cytology,enzymology Oligopeptides/pharmacology Rabbits Rats Rats, Wistar Sweden Tumor Cells, Cultured

Chemicals

Amyloid beta-Peptides Amyloid beta-Protein Precursor Cysteine Proteinase Inhibitors Enzyme Inhibitors Enzyme Precursors Excitatory Amino Acid Agonists Oligopeptides acetyl-aspartyl-glutamyl-valyl-aspartal L 709049 Aspartic Acid Amyloid Precursor Protein Secretases Endopeptidases CASP3 protein, human Casp3 protein, mouse Casp3 protein, rat Caspase 3 Caspases Aspartic Acid Endopeptidases BACE1 protein, human Bace1 protein, mouse Kainic Acid Camptothecin

Authors & Affiliations

19 authors, click to expand affiliations / ORCID

Gervais F G

Department of Pharmacology, Biochemistry, and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Merck Research Laboratories, Kirkland, Quebec, Canada.

Xu D

Robertson G S

Vaillancourt J P

Zhu Y

Huang J

LeBlanc A

Smith D

Rigby M

Shearman M S

Clarke E E

Zheng H

Van Der Ploeg L H

Ruffolo S C

Thornberry N A

Xanthoudakis S

Zamboni R J

Roy S

Nicholson D W

Article Info

Journal

Cell

Abbr.

Cell

ISSN

0092-8674

DOI

10.1016/s0092-8674(00)80748-5

Published

1999-04-30

Pages

395-406

Language

English

Region

United States

NLM ID

0413066

Subset

External Links

PubMed source DOI: 10.1016/s0092-8674(00)80748-5 View journal details

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Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation.

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