Activation of caspase-8 in the Alzheimer's disease brain.
Recent studies support the activation of apoptotic pathways in the Alzheimer's disease (AD) brain. Neurons committed to apoptosis may do so by either activation of a receptor-mediated pathway employing caspase-8 or through an alternative mitochondrial pathway involving oxidative stress. In the present study, the role of caspase-8 in the AD brain was examined by designing a caspase-cleavage site-directed antibody to one of the active fragments of caspase-8. In vitro analysis with this antibody, termed CASP-8p18, demonstrated that it recognized the active 18-kDa fragment of caspase-8 but not the precursor protein. In vivo immunohistochemical analysis using hippocampal tissue sections from AD or aged-matched control brains demonstrated CASP-8p18 immunolabeling of neurons in all AD cases, whereas little staining was observed in controls. These results were confirmed using a commercially available antibody that, like the CASP-8p18 antibody reacts only with the 18-kDa fragment of caspase-8 and not full-length caspase-8. As with CASP-8p18 antibody, the commercial antibody-labeled neurons in all AD cases, while showing a relative paucity of staining in representative control cases. Labeling of CASP-8p18 within tangle-bearing neurons was observed in double-labeling studies with AT8 or PHF-1, both markers for neurofibrillary tangles (NFTs). In addition, using a caspase-cleavage site-directed antibody that recognizes cleavage products of caspase-3 showed colocalization of this antibody with the CASP-8p18 antibody within NFTs. These results suggest a role for caspase-8 and the receptor-mediated apoptotic pathway as a mechanism leading to the activation of caspase-3 within neurons of the AD brain.
Rohn
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Department of Biology, Boise State University, Boise, Idaho 83725, USA.
Head
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Nesse
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Cotman
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Cribbs
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D000368:Aged; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000918:Antibody Specificity; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000276:immunology / Q000378:metabolism*; D002451:Cell Compartmentation / Q000276:immunology; D004285:Dogs; D018728:Entorhinal Cortex / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006367:HeLa Cells; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D013049:Spectrin
D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D008840:Microfilament Proteins; D013049:Spectrin; C085349:PHF-1 monoclonal antibody; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human