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 early-onset autosomal dominant inherited forms of Alzheimer's disease. Recent findings suggest that PS-1 mutations may sensitize neurons to apoptosis induced by trophic factor withdrawal and exposure to amyloid β-peptide (Aβ). 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). Elevations of the intracellular Ca²⁺ concentration and generation of reactive oxygen species induced by Aβ, and potentiated by mutant PS-1, were suppressed in calbindin- overexpressing cells. Impairment of mitochondrial function by Aβ (which preceded apoptosis) was exacerbated by PS-1 mutations and was largely prevented by culbindin. 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.