Abstract

Exaggerated intracellular Ca2+ signaling is a robust proximal phenotype observed in cells expressing familial Alzheimer's disease (FAD)-causing mutant presenilins (PSs). The mechanisms that underlie this phenotype are controversial and their in vivo relevance for AD pathogenesis is unknown. Here, we used a genetic approach to identify the mechanisms involved and to evaluate their role in the etiology of AD in two FAD mouse models. Genetic reduction of the type 1 inositol trisphosphate receptor (InsP(3)R1) by 50% normalized exaggerated Ca2+ signaling observed in cortical and hippocampal neurons in both animal models. In PS1M146V knock-in mice, reduced InsP(3)R1 expression restored normal ryanodine receptor and cAMP response element-binding protein (CREB)-dependent gene expression and rescued aberrant hippocampal long-term potentiation (LTP). In 3xTg mice, reduced InsP(3)R1 expression profoundly attenuated amyloid beta accumulation and tau hyperphosphorylation and rescued hippocampal LTP and memory deficits. These results indicate that exaggerated Ca2+ signaling, which is associated with FAD PS, is mediated by InsP(3)R and contributes to disease pathogenesis in vivo. Targeting the InsP(3) signaling pathway could be considered a potential therapeutic strategy for patients harboring mutations in PS linked to AD.