Enhanced ROS generation mediated by Alzheimer's disease presenilin regulation of InsP3R Ca2+ signaling.

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 (Ca(2+)) homeostasis by proximal mechanisms independent of amyloid production by dramatically enhancing gating of the inositol trisphosphate receptor (InsP(3)R) intracellular Ca(2+) release channel by a gain-of-function effect that mirrors genetics of FAD and is independent of secretase activity. Electrophysiological recordings of InsP(3)R in FAD patient B cells, cortical neurons of asymptomatic PS1-AD mice, and other cells revealed they have higher occupancy in a high open probability burst mode, resulting in enhanced Ca(2+) signaling. Exaggerated Ca(2+) signaling through this mechanism results in enhanced generation of reactive oxygen species, believed to be an important component in AD pathogenesis. Exaggerated Ca(2+) signaling through InsP(3)R-PS interaction is a disease specific and robust proximal mechanism in AD that may contribute to the pathology of AD by enhanced generation of reactive oxygen species.