Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid β-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 immunocytochemical studies indicate that PS-1 is localized to endoplasmic reticulum (ER). We report that expression of PS-1 mutation L286V in cultured PC12 cells exaggerates Ca²⁺ responses to agonists (carbachol and bradykinin) that induce Ca²⁺ release from ER. Cells expressing L286V exhibit enhanced elevations of [Ca²⁺](i) following exposure to amyloid β-peptide (Aβ) and increased vulnerability to Aβ toxicity. An antagonist of voltage-dependent calcium channels (nifedipine), and a blocker of Ca²⁺ release from ER (dantrolene), counteract the adverse consequences of the PS-1 mutation. By perturbing Ca²⁺ homeostasis, PS-1 mutations may sensitize neurons to Aβ-induced apoptosis.