Research ArticleAlzheimer’s Disease

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

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Science Signaling  06 Sep 2016:
Vol. 9, Issue 444, pp. ra89
DOI: 10.1126/scisignal.aaf1371

Cleaving toward memory loss

The senile dementia that occurs in Alzheimer’s disease is devastating for patients and their families. Neuronal shape dictates learning and memory, and neurons from mouse models of Alzheimer’s disease show altered neuronal morphology and dysregulated Ca2+ signaling. Tong et al. found that the endoplasmic reticulum Ca2+ sensor STIM1 was subjected to excess cleavage and inactivation by forms of presenilin 1 (PS1) with familial Alzheimer’s disease–associated mutations. Hippocampal neurons expressing a mutant PS1 showed dysregulated Ca2+ signaling and altered neuronal morphology, both of which were rescued by inhibiting cleavage by PS1 or overexpressing STIM1. Thus, the cleavage of STIM1 by PS1 may contribute to the memory loss that is characteristic of Alzheimer’s disease.