CALBINDIN D28K BLOCKS THE PROAPOPTOTIC ACTIONS OF MUTANT PRESENILIN-1- REDUCED OXIDATIVE STRESS AND PRESERVED MITOCHONDRIAL-FUNCTION

Mutations in the presenilin 1 (PS-1) gene account for many cases of ea rly-onset autosomal dominant inherited forms of Alzheimer's disease. R ecent findings suggest that PS-1 mutations may sensitize neurons to ap optosis induced by trophic factor withdrawal and exposure to amyloid b eta-peptide (A beta). We now report that overexpression of the calcium -binding protein calbindin D28k prevents apoptosis in cultured neural cells expressing mutant PS-1 (L286V and M146V missense mutations). Ele vations of the intracellular Ca2+ concentration and generation of reac tive oxygen species induced by A beta, and potentiated by mutant PS-1, were suppressed in calbindin-overexpressing cells. Impairment of mito chondrial function by AP (which preceded apoptosis) was exacerbated by PS-1 mutations and was largely prevented by calbindin. These findings suggest that PS-1 mutations render neurons vulnerable to apoptosis by a mechanism involving destabilization of cellular calcium homeostasis , which leads to oxidative stress and mitochondrial dysfunction.