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

Antioxid Redox Signal. 2011 Apr 1;14(7):1225-35. doi: 10.1089/ars.2010.3421. Epub 2010 Dec 2.

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 (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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Animals
  • B-Lymphocytes / pathology
  • B-Lymphocytes / physiology
  • Calcium Signaling*
  • Cell Line
  • Humans
  • Hydrogen Peroxide / metabolism
  • Inositol 1,4,5-Trisphosphate / pharmacology
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Ion Channel Gating
  • Membrane Potentials
  • Mice
  • Mutation
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism*
  • Presenilin-2 / genetics
  • Presenilin-2 / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism

Substances

  • Inositol 1,4,5-Trisphosphate Receptors
  • Presenilin-1
  • Presenilin-2
  • Reactive Oxygen Species
  • Recombinant Fusion Proteins
  • Inositol 1,4,5-Trisphosphate
  • Hydrogen Peroxide