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The Journal of Neuroscience, August 1, 1998, 18(15):5869-5880

Increased Production of Amyloid Precursor Protein Provides a Substrate for Caspase-3 in Dying Motoneurons

Natalie Y. Barnes1, Ling Li1, Kazuaki Yoshikawa2, Lawrence M. Schwartz3, Ronald W. Oppenheim1, and Carolanne E. Milligan1

1 Department of Neurobiology and Anatomy and the Neuroscience Program, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, 2 Division of Regulation of Macromolecular Functions, Institute for Protein Research, Osaka University, Suita, Osaka 565, Japan, and 3 Department of Biology, University of Massachusetts, Amherst, Massachusetts 01003

Biochemical and molecular mechanisms of neuronal cell death are currently an area of intense research. It is well documented that the lumbar spinal motoneurons of the chick embryo undergo a period of naturally occurring programmed cell death (PCD) requiring new gene expression and activation of caspases. To identify genes that exhibit changed expression levels in dying motoneurons, we used a PCR-based subtractive hybridization protocol to identify messages uniquely expressed in motoneurons deprived of trophic support as compared with their healthy counterparts. We report that one upregulated message in developing motoneurons undergoing cell death is the mRNA for amyloid precursor protein (APP). Increased levels of APP and beta -amyloid protein are also detected within dying motoneurons. The predicted peptide sequence of APP indicates two potential cleavage sites for caspase-3 (CPP-32), a caspase activated in dying motoneurons. When peptide inhibitors of caspase-3 are administered to motoneurons destined to undergo PCD, decreased levels of APP protein and greatly reduced beta -amyloid production are observed. Furthermore, we show that APP is cleaved by caspase-3. Our results suggest that differential gene expression results in increased levels of APP, providing a potential substrate for one of the cell death-activated caspases that may ultimately cause the demise of the cell. These results, combined with information on the toxic role of APP and its proteolytic by-product beta -amyloid, in the neurodegenerative disease Alzheimer's, suggest that events of developmental PCD may be reactivated in early stages of pathological neurodegeneration.

Key words: apoptosis; Alzheimer's disease; amyloid precursor protein; beta -amyloid; CPP-32; ICE-like proteases

Copyright © 1998 Society for Neuroscience  0270-6474/98/18155869-12$05.00/0


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