Gamma-secretase cleaves stromal interaction molecule 1 induces capacitative calcium entry deficits in familial Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is the most common form of dementia and mounting evidence suggests calcium (Ca2+) disruption is its proximal pathogenic origin. Ca2+ dysregulation observed in cells expressing familial Alzheimer’s disease (FAD)- causing presenilins (PS) has been attributed to the exaggerated Ca2+ release and the attenuated store-operated Ca2+ entry (also known as capacitative Ca2+ entry, CCE). Several mechanisms have been proposed for the exaggerated Ca2+ release, yet the underlying molecular mechanisms for attenuated CCE remain elusive. In this study we employed Ca2+ imaging, FRET microscopy, in situ proximity ligation assay, in vitro γ-secretase cleavage assay and primary neuronal culture to delineate the mechanism for CCE attenuation and its linkage to AD pathology. We showed that the attenuation of CCE depends upon PS-associated γ-secretase activity. PS1 and STIM1 interact in human neuroblastoma SH-SY5Y cells, and mutant PS1 enhances γ-secretase cleavage of STIM1 in the transmembrane domain that has high similarity with amyloid precursor protein. Furthermore, FAD PS1-induced CCE attenuation destabilizes mature dendritic spines that are rescued by γ-secretase inhibition or overexpression of STIM1. Our results suggest a molecular mechanism of CCE deficits in which FAD-mutant PS1 enhances γ-secretase cleavage of STIM1, reducing recruitment of Orai1 that results in impaired CCE. These findings indicate a physiological role of PS1/γ-secretase in modulating the availability of STIM1 for CCE, and suggest that identification of STIM1 as a substrate of γ-secretase provides a novel therapeutic target for the treatment of AD.