LACK OF SPECIFIC ASSOCIATION OF PRESENILIN-1 (PS-1) PROTEIN WITH PLAQUES AND TANGLES IN ALZHEIMERS-DISEASE

Missense mutations in the presenilin-1 (PS-I) gene are causally relate d to the majority of familial early-onset Alzheimer's disease (FAD). P S-1 immunohistochemical expression in normal human brain and in brains with Alzheimer's disease (AD) has so far been controversial. Here, we report a study of PS-1 expression in brains, cell lines and periphera l blood mononuclear cells using a panel of well characterized PS-1-spe cific antibodies. These antibodies were characterized by immunofluores cent staining of PS-1 transfectants followed by flow cytometric analys is. In human brain, widespread neuronal staining was observed. PS-1 im munoreactivity was primarily confined to neuronal cell bodies and prox imal dendrites. Weaker staining of microglia was also detected, in acc ord with the finding of PS-1 immunoreactivity in monocytes. PS-1 expre ssion is not particularly associated with neurons either containing or spared from neurofibrillary tangles, nor with senile plaques. The lev el of PS-I expression does not differ between normal and AD brains. Im munoprecipitation from AD, FAD and control brains revealed only a 32 k Da N-terminal fragment and an 18-20 kDa C-terminal fragment. Little or no full length PS-1was detected. The enriched presence of PS-1 in neu rons implies an important role in neuronal function, however, the lack of apparent association of its expression with AD pathology signifies the need for a better understanding of its pathophysiological role. ( C) 1998 Elsevier Science B.V.