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Previous Article | Next Article
The Journal of Neuroscience, December 1, 1998, 18(23):9790-9799
Overexpression in Neurons of Human Presenilin-1 or a Presenilin-1 Familial Alzheimer Disease Mutant Does Not Enhance Apoptosis
Sherry Bursztajn1, Richard DeSouza2, Donna L. McPhie3, S. A. Berman1, Junichi Shioi4, Nikolaos K. Robakis4, and Rachael L. Neve3 1 Department of Psychiatry and Program in Neuroscience, Harvard Medical School, Belmont, Massachusetts 02478, 2 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, 3 Department of Genetics, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478, and 4 Department of Psychiatry and Fishberg Research Center for Neurobiology, Mount Sinai School of Medicine, New York, New York 10029
Programmed cell death, or apoptosis, has been implicated in Alzheimer's disease (AD). DNA damage was assessed in primary cortical neurons infected with herpes simplex virus (HSV) vectors expressing the familial Alzheimer's disease (FAD) gene presenilin-1 (PS-1) or an FAD mutant of this gene, A246E. After infection, immunoreactivity for PS-1 was shown to be enhanced in infected cells. The infected cells exhibited no cytotoxicity, as evaluated by trypan blue exclusion and mitochondrial function assays. Quantitative analysis of cells that were immunohistochemically labeled using a Klenow DNA fragmentation assay or the TUNEL method revealed no enhancement of apoptosis in PS-1-infected cells. This result was confirmed using assays for chromatin condensation and for DNA fragmentation. Expression of PS-1 protected against induction of apoptosis in the cortical neurons by etoposide or staurosporine. The specificity of this phenotype was demonstrated by the fact that cortical cultures infected with recombinant HSV vectors expressing the amyloid precursor protein (APP-695) showed, in contrast, a significant increase in the number of apoptotic cells and an increase in DNA fragmentation for all parameters tested. Our results indicate that overexpression of wild-type or A246E mutant PS-1 does not enhance apoptosis in postmitotic cortical cells and suggest that the previously reported enhancement of apoptosis by presenilins may be dependent on cell type.
Key words: apoptosis; neurodegeneration; presenilin; amyloid precursor protein; DNA fragmentation; Alzheimer's disease
Copyright © 1998 Society for Neuroscience 0270-6474/98/18239790-10$05.00/0
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