PRESENILIN-1 MUTATION ALTERS NGF-INDUCED NEURITE OUTGROWTH, CALCIUM HOMEOSTASIS, AND TRANSCRIPTION FACTOR (AP-1) ACTIVATION IN PC12 CELLS

Mutations in the presenilin-1 (PS-1) gene are responsible for many cas es of autosomal dominant early-onset inherited Alzheimer's disease (AD ), PS-1 is expressed in neurons where it is localized primarily to the endoplasmic reticulum (ER); the normal function of PS-1 and its patho genic mechanism in AD are not known, We now report that expression of an AD-linked human PS-1 mutation (L286V) in PC12 cells results in aber rant differentiation responses to nerve growth factor (NGF). The exten t of neurite outgrowth during a 10-day period of exposure to NGF was s ignificantly reduced In lines stably expressing mutant PS-1. NGF induc ed a prolonged elevation of intracellular calcium levels which was sig nificantly enhanced in cells expressing mutant PS-1. Induction of DNA binding activity of the transcription factor AP-1 by NGF was markedly suppressed in cells expressing mutant PS-1. Collectively, these findin gs demonstrate that a PS-1 mutation alters cellular signaling systems associated with NGF-induced differentiation in PC12 cells. Altered res ponsivity to neurotrophic factors could play a role in the pathogenesi s of neuritic degeneration and cell death in human carriers of PS-1 mu tations. (C) 1998 Wiley-Liss, Inc.