ALZHEIMERS PS-1 MUTATION PERTURBS CALCIUM HOMEOSTASIS AND SENSITIZES PC12 CELLS TO DEATH INDUCED BY AMYLOID BETA-PEPTIDE

MUTATIONS in the presenilin-1 (PS-1) gene on chromosome 14 are linked to autosomal dominant early-onset Alzheimer's disease. The amino acid sequence of PS-1 predicts an integral membrane protein and immunocytoc hemical studies indicate that PS-1 is localized to endoplasmic reticul um (ER). We report that expression of PS-1 mutation L286V in cultured PC12 cells exaggerates Ca2+ responses to agonists (carbachol and brady kinin) that induce Ca2+ release from ER. Cells expressing L286V exhibi t enhanced elevations of [Ca2+](i) following exposure to amyloid beta- peptide (A(b)eta) and increased vulnerability to A beta toxicity. An a ntagonist of voltage-dependent calcium channels (nifedipine), and a bl ocker of Ca2+ release from ER (dantrolene), counteract the adverse con sequences of the PS-1 mutation. By perturbing Ca2+ homeostasis, PS-1 m utations may sensitize neurons to A beta-induced apoptosis.