Ca2+ Influx through Store-operated Ca2+ Channels Reduces Alzheimer Disease β-Amyloid Peptide Secretion

Alzheimer disease (AD), the leading cause of dementia, is characterized by the accumulation of beta-amyloid peptides (A beta) in senile plaques in the brains of affected patients. Many cellular mechanisms are thought to play important roles in the development and progression of AD. Several lines of evidence point to the dysregulation of Ca2+ homeostasis as underlying aspects of AD pathogenesis. Moreover, direct roles in the regulation of Ca2+ homeostasis have been demonstrated for proteins encoded by familial AD-linked genes such as PSEN1, PSEN2, and APP, as well as A beta peptides. Whereas these studies support the hypothesis that disruption of Ca2+ homeostasis contributes to AD, it is difficult to disentangle the effects of familial AD-linked genes on A beta production from their effects on Ca2+ homeostasis. Here, we developed a system in which cellular Ca2+ homeostasis could be directly manipulated to study the effects on amyloid precursor protein metabolism and A beta production. We overexpressed stromal interaction molecule 1 (STIM1) and Orai1, the components of the store-operated Ca2+ entry pathway, to generate cells with constitutive and store depletion-induced Ca2+ entry. We found striking effects of Ca2+ entry induced by overex-pression of the constitutively active STIM1(D76A) mutant on amyloid precursor protein metabolism. Specifically, constitutive activation of Ca2+ entry by expression of STIM1D76A significantly reduced A beta secretion. Our results suggest that disruptions in Ca2+ homeostasis may influence AD pathogenesis directly through the modulation of A beta production.