NEURONAL EXPRESSION OF BETA-AMYLOID PRECURSOR PROTEIN ALZHEIMER MUTATIONS CAUSES INTRACELLULAR ACCUMULATION OF A C-TERMINAL FRAGMENT CONTAINING BOTH THE AMYLOID-BETA AND CYTOPLASMIC DOMAINS

Five different Alzheimer mutations of the beta-amyloid precursor prote in (APP) were expressed in neurons via recombinant herpes simplex viru s (HSV) vectors, and the levels of APP metabolites were quantified, Th e predominant intracellular accumulation product was a C-terminal frag ment of APP that co-migrated with the protein product of an HSV recomb inant expressing the C-terminal 100 amino acids (C100) of APP, which i s known to cause neurodegeneration. Fractionation studies revealed tha t the C-terminal fragment generated by expression of the Alzheimer mut ations, Like C100, partitioned into membrane fractions and was particu larly enriched in synaptosomes. The processing abnormality caused by e xpression of the Alzheimer mutations occurs predominantly in neurons. Expression of these mutations or of C100 alone in neurons caused incre ased secretion of A beta relative to that of neurons infected with wil d type APP recombinant vectors, These data show that expression of APP mutations that cause familial Alzheimer's disease increases the intra cellular accumulation of potentially amyloidogenic and neurotoxic C-te rminal fragments of APP in neurons.