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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Disease
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Alzheimer Disease / enzymology*
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Alzheimer Disease / genetics
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Alzheimer Disease / pathology
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Amyloid Precursor Protein Secretases
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism*
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism*
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Amyloidosis / enzymology*
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Amyloidosis / genetics
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Amyloidosis / pathology
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Aspartic Acid
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Aspartic Acid Endopeptidases
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Brain Diseases / chemically induced
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Brain Diseases / enzymology
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Brain Diseases / pathology
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Camptothecin / pharmacology
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Caspase 3
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Caspases / analysis
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Caspases / metabolism*
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Cysteine Proteinase Inhibitors / pharmacology
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Endopeptidases / genetics
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Enzyme Inhibitors / pharmacology
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Enzyme Precursors / analysis
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Enzyme Precursors / metabolism
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Excitatory Amino Acid Agonists
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Hippocampus / cytology
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Humans
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In Situ Nick-End Labeling
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Kainic Acid
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Leukemia, Erythroblastic, Acute
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Male
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Mice
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Mice, Inbred C57BL
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Mutation / physiology
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Neurons / chemistry
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Neurons / cytology
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Neurons / enzymology
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Oligopeptides / pharmacology
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Rabbits
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Rats
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Rats, Wistar
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Sweden
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Tumor Cells, Cultured
Substances
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Amyloid beta-Peptides
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Amyloid beta-Protein Precursor
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Cysteine Proteinase Inhibitors
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Enzyme Inhibitors
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Enzyme Precursors
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Excitatory Amino Acid Agonists
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Oligopeptides
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acetyl-aspartyl-glutamyl-valyl-aspartal
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L 709049
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Aspartic Acid
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Amyloid Precursor Protein Secretases
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Endopeptidases
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CASP3 protein, human
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Casp3 protein, mouse
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Casp3 protein, rat
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Caspase 3
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Caspases
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Aspartic Acid Endopeptidases
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BACE1 protein, human
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Bace1 protein, mouse
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Kainic Acid
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Camptothecin