DIFFERENT EFFECTS OF ALZHEIMER-ASSOCIATED MUTATIONS OF PRESENILIN-1 ON ITS PROCESSING

Presenilin 1 (PS 1) shows missense mutations in most early-onset famil ial Alzheimer's disease (FAD). Transfection of cDNA for wild type PS 1 into rat pheochromocytoma PC12 cells generated a 47 kDa full-size PS 1 protein, which was processed into a 28 kDa N-terminal fragment and a 19 kDa C-terminal fragment. We prepared selected Alzheimer-associated mutations (Gly384Ala, Leu392Val, and Cys410Tyr) of PS 1, which locali zed after a possible cleavage site. By transient expression in PC12 ce lls and rat glioma cell line, C6, we examined their influence on the p rocessing of PS 1. Cys410Tyr inhibited proteolytic processing of PS 1, while Gly384Ala and Leu392Val did not. Thus, the Alzheimer related mu tations can be divided into two groups in terms of their effect on the proteolytic cleavage of PS 1. (C) 1997 Elsevier Science Ireland Ltd.