Gain-of-function enhancement of InsP3 receptor modal gating by familial Alzheimer’s disease-linked presenilin mutants in human cells and mouse neurons

摘要

Familial Alzheimer’s disease (FAD) is caused by mutations in amyloid precursor protein or presenilins (PS1, PS2). Many FAD-linked PS mutations affect intracellular calcium (Ca²⁺) homeostasis by mechanisms proximal to and independent of amyloid production, although the molecular details are controversial. Here, we demonstrate that several FAD-causing PS mutants enhance gating of the inositol trisphosphate receptor (InsP3R) Ca²⁺ release channel by a gain-of-function effect that mirrors the genetics of FAD and is independent of secretase activity. In contrast, wild type PS or PS mutants that cause frontotemporal dementia have no such effect. FAD PS alter InsP3R channel gating by modal switching. Recordings of endogenous InsP3R in lymphoblasts derived from individuals with FAD or cortical neurons of asymptomatic PS1-AD mice revealed they have higher occupancy in a high open probability burst mode compared to that of InsP3R in cells with wild-type PS, resulting in enhanced Ca²⁺ signaling. These results indicate that exaggerated Ca²⁺ signaling through InsP3R-PS interaction is a disease-specific and robust proximal mechanism in FAD.