PRESENILIN-1 PROTEIN EXPRESSION IN FAMILIAL AND SPORADIC ALZHEIMERS-DISEASE

Mutations of the presenilin PS1 and PS2 genes are closely linked to ag gressive forms of early-onset (<60 years) familial Alzheimer's disease . A highly specific monoclonal antibody was developed to identify and characterize the native PS1 protein. Western blot analyses revealed a predominant 32-kd immunoreactive polypeptide in a variety of samples, including PC12 cells transfected with human PS1 complementary DNA, bra in biopsy specimens from demented patients, and postmortem samples of frontal neocortex from early-onset familiar Alzheimer's disease cases (PS1 and PS2), late-onset sporadic Alzheimer's disease cases, and case s of other degenerative disorders. This truncated polypeptide contains the N-terminus of PS1 and appeared unchanged across cases. In 2 early -onset cases linked to missense mutations in the PS1 gene, a PS1 immun oreative protein (similar to 49 kd) accumulated in the frontal cortex. This protein was similar in size to full-length PS1 protein present i n transfected cells overexpressing PS1 complementary DNA, and in lymph ocytes from an affected individual with a deletion of exon 9 of the PS 1 gene, suggesting that mutations of the PS1 gene perturb the endoprot eolytic processing of the protein. Immunohistochemical studies of cont rol brains revealed that PS1 is expressed primarily in neurons, with t he protein localized in the soma and dendritic processes. In contrast, PS1 showed striking localization to the neuropathology in early-onset familial Alzheimer's disease and sporadic Alzheimer's disease cases. PS1 immunoreativity was present in the neuritic component of senile pl aques as well as in neurofibrillary tangles. Localization of PS1 immun oreactivity in familial and sporadic Alzheimer's disease suggests that genetically heterogeneous forms of the disease share a common pathoph ysiology involving PS1 protein.