OVEREXPRESSION IN NEURONS OF HUMAN PRESENILIN-1 OR A PRESENILIN-1 FAMILIAL ALZHEIMER-DISEASE MUTANT DOES NOT ENHANCE APOPTOSIS

Programmed cell death, or apoptosis, has been implicated in Alzheimer' s disease (AD). DNA damage was assessed in primary cortical neurons in fected with herpes simplex virus (HSV) vectors expressing the familiar Alzheimer's disease (FAD) gene presenilin-1 (PS-1) or an FAD mutant o f this gene, A246E. After infection, immunoreactivity for PS-1 was sho wn to be enhanced in infected cells. The infected cells exhibited no c ytotoxicity, as evaluated by trypan blue exclusion and mitochondrial f unction assays. Quantitative analysis of cells that were immunohistoch emically labeled using a Klenow DNA fragmentation assay or the TUNEL m ethod revealed no enhancement of apoptosis in PS-1-infected cells. Thi s 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 s pecificity of this phenotype was demonstrated by the fact that cortica l cultures infected with recombinant HSV vectors expressing the amyloi d precursor protein (APP-695) showed, in contrast, a significant incre ase in the number of apoptotic cells and an increase in DNA fragmentat ion for all parameters tested. Our results indicate that overexpressio n of wild-type or A246E mutant PS-1 does not enhance apoptosis in post mitotic cortical cells and suggest that the previously reported enhanc ement of apoptosis by presenilins may be dependent on cell type.