Abstract
Familial Alzheimer's disease (FAD) is caused by mutations in amyloid precursor protein and presenilins (PS1, PS2). Many FAD-linked PS mutations affect intracellular calcium (Ca2+) homeostasis by proximal mechanisms independent of amyloid production, although the molecular details are controversial. Here, we demonstrate that several FAD-causing PS dramatically enhance gating of the inositol trisphosphate receptor (InsP3R) intracellular Ca2+ release channel measured in native endoplasmic reticulum membranes by nuclear patch clamp electrophysiology. In contrast, wild type or mutant PS that cause frontotemporal dementia have no such effect. FAD PS alter InsP3R channel gating by modal switching to a high open probability burst mode. Single channel recordings of endogenous InsP3R in FAD patient B cells as well as cortical neurons of asymptomatic PS1-AD mice revealed they have higher occupancy in the burst mode than controls, resulting in enhanced intracellular Ca2+ signals. These results indicate that exaggerated Ca2+ signaling through InsP3R-PS interaction is a disease specific and robust proximal mechanism in AD.
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