title: Overexpression in neurons of human presenilin-1 or a presenilin-1 familial Alzheimer disease mutant does not enhance apoptosis.
abstract: 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.
authors.affiliation: Department of Psychiatry and Program in Neuroscience, Harvard Medical School, Belmont, Massachusetts 02478, USA. sbursz@lsumc.edu
authors.forename: S
authors.initials: S
authors.lastname: Bursztajn
authors.forename: R
authors.initials: R
authors.lastname: DeSouza
authors.forename: D L
authors.initials: DL
authors.lastname: McPhie
authors.forename: S A
authors.initials: SA
authors.lastname: Berman
authors.forename: J
authors.initials: J
authors.lastname: Shioi
authors.forename: N K
authors.initials: NK
authors.lastname: Robakis
authors.forename: R L
authors.initials: RL
authors.lastname: Neve
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D006690:Bisbenzimidazole / Q000494:pharmacology; D002470:Cell Survival / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology; D053938:DNA Fragmentation / Q000502:physiology; D005456:Fluorescent Dyes / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D020287:In Situ Nick-End Labeling; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000502:physiology; D009410:Nerve Degeneration / Q000503:physiopathology; D009474:Neurons / Q000502:physiology*; D053764:Presenilin-1; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D005456:Fluorescent Dyes; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011994:Recombinant Proteins; D006690:Bisbenzimidazole