Gain-of-Function Enhancement of IP ₃ Receptor Modal Gating by Familial Alzheimer’s Disease–Linked Presenilin Mutants in Human Cells and Mouse Neurons

Abstract

Familial Alzheimer's disease (FAD) is caused by mutations in amyloid precursor protein or presenilins (PS1 and PS2). Many FAD-linked PS mutations affect intracellular calcium (Ca(2+)) homeostasis by mechanisms proximal to and independent of amyloid production, although the molecular details are controversial. We found that several FAD-causing PS mutants enhance gating of the inositol trisphosphate receptor (IP(3)R) Ca(2+) release channel by a gain-of-function effect that mirrored the genetics of FAD and was independent of secretase activity. In contrast, wild-type PS or PS mutants that cause frontotemporal dementia had no such effect. FAD-causing PS mutants altered the modes in which the IP(3)R channel gated. Recordings of endogenous IP(3)R in lymphoblasts derived from individuals with FAD or cortical neurons of asymptomatic PS1-AD mice revealed that they were more likely than IP(3)R in cells with wild-type PS to dwell in a high open-probability burst mode, resulting in enhanced Ca(2+) signaling. These results indicate that exaggerated Ca(2+) signaling through IP(3)R-PS interaction is a disease-specific and robust proximal mechanism in FAD.