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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: M800007-MCP200v1 7/8/1541    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Glossary Google Scholar Articles by Klaiman, G. Articles by LeBlanc, A. C. PubMed PubMed Citation Articles by Klaiman, G. Articles by LeBlanc, A. C. Social Bookmarking                      What's this?

Molecular & Cellular Proteomics 7:1541-1555, 2008.
© 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

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Research

Targets of Caspase-6 Activity in Human Neurons and Alzheimer Disease^*,S

Guy Klaiman^,,¶, Tracy L. Petzke^,¶, Jennifer Hammond and Andréa C. LeBlanc^,,||

From The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Ch. Cote Ste-Catherine, Montreal, Quebec H3T 1E2, Canada and the Department of Neurology and Neurosurgery, McGill University, 3775 University St., Montreal, Quebec H3A 2B4, Canada

Caspase-6 activation occurs early in Alzheimer disease and sometimes precedes the clinical manifestation of the disease in aged individuals. The active Caspase-6 is localized in neuritic plaques, in neuropil threads, and in neurofibrillary tangles containing neurons that are not morphologically apoptotic in nature. To investigate the potential consequences of the activation of Caspase-6 in neurons, we conducted a proteomics analysis of Caspase-6-mediated cleavage of human neuronal proteins. Proteins from the cytosolic and membrane subcellular compartments were treated with recombinant active Caspase-6 and compared with undigested proteins by two-dimensional gel electrophoresis. LC/MS/MS analyses of the proteins that were cleaved identified 24 different potential protein substrates. Of these, 40% were cytoskeleton or cytoskeleton-associated proteins. We focused on the cytoskeleton proteins because these are critical for neuronal structure and function. Caspase-6 cleavage of -Tubulin, -Actinin-4, Spinophilin, and Drebrin was confirmed. At least one Caspase-6 cleavage site was identified for Drebrin, Spinophilin, and -Tubulin. A neoepitope antiserum to -Tubulin cleaved by Caspase-6 immunostained neurons, neurofibrillary tangles, neuropil threads, and neuritic plaques in Alzheimer disease and co-localized with active Caspase-6. These results imply that the early and neuritic activation of Caspase-6 in Alzheimer disease could disrupt the cytoskeleton network of neurons, resulting in impaired neuronal structure and function in the absence of cell death. This study provides novel insights into the pathophysiology of Alzheimer disease.

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