Familial Alzheimer's disease-associated presenilin 1 mutants promote γ-secretase cleavage of STIM1 to impair store-operated Ca²⁺ entry

Some forms of familial Alzheimer's disease (FAD) are caused by mutations in presenilins (PSs), catalytic components of a γ-secretase complex that cleaves target proteins, including amyloid precursor protein (APP). Calcium (Ca²⁺) dysregulation in cells with these FAD-causing PS mutants has been attributed to attenuated store-operated Ca²⁺ entry [SOCE; also called capacitative Ca²⁺ entry (CCE)]. CCE occurs when STIM1 detects decreases in Ca²⁺ in the endoplasmic reticulum (ER) and activates Orai channels to replenish Ca²⁺ stores in the ER.We showed that CCE was attenuated by PS1-associated γ-secretase activity. Endogenous PS1 and STIM1 interacted in human neuroblastoma SH-SY5Y cells, patient fibroblasts, and mouse primary cortical neurons. Forms of PS1 with FAD-associated mutations enhanced γ-secretase cleavage of the STIM1 transmembrane domain at a sequence that was similar to the γ-secretase cleavage sequence of APP. Cultured hippocampal neurons expressing mutant PS1 had attenuated CCE that was associated with destabilized dendritic spines, which were rescued by either γ-secretase inhibition or overexpression of STIM1. Our results indicate that γ-secretase activity may physiologically regulate CCE by targeting STIM1 and that restoring STIM1 may be a therapeutic approach in AD.