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  • Title: Presenilin-1 mutation alters NGF-induced neurite outgrowth, calcium homeostasis, and transcription factor (AP-1) activation in PC12 cells.
    Author: Furukawa K, Guo Q, Schellenberg GD, Mattson MP.
    Journal: J Neurosci Res; 1998 Jun 01; 52(5):618-24. PubMed ID: 9632318.
    Abstract:
    Mutations in the presenilin-1 (PS-1) gene are responsible for many cases 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 pathogenic 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 aberrant differentiation responses to nerve growth factor (NGF). The extent of neurite outgrowth during a 10-day period of exposure to NGF was significantly reduced in lines stably expressing mutant PS-1. NGF induced a prolonged elevation of intracellular calcium levels which was significantly 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 findings demonstrate that a PS-1 mutation alters cellular signaling systems associated with NGF-induced differentiation in PC12 cells. Altered responsivity to neurotrophic factors could play a role in the pathogenesis of neuritic degeneration and cell death in human carriers of PS-1 mutations.
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