Calbindin D28K blocks the proapoptotic actions of mutant presenilin 1: Reduced oxidative stress and preserved mitochondrial function

Qing Guo, Sylvia Christakos, Nic Robinson, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the presenilin 1 (PS-1) gene account for many cases of early-onset autosomal dominant inherited forms of Alzheimer's disease. Recent findings suggest that PS-1 mutations may sensitize neurons to apoptosis induced by trophic factor withdrawal and exposure to amyloid β-peptide (Aβ). We now report that overexpression of the calcium-binding protein calbindin D28k prevents apoptosis in cultured neural cells expressing mutant PS-1 (L286V and M146V missense mutations). Elevations of the intracellular Ca2+ concentration and generation of reactive oxygen species induced by Aβ, and potentiated by mutant PS-1, were suppressed in calbindin- overexpressing cells. Impairment of mitochondrial function by Aβ (which preceded apoptosis) was exacerbated by PS-1 mutations and was largely prevented by culbindin. These findings suggest that PS-1 mutations render neurons vulnerable to apoptosis by a mechanism involving destabilization of cellular calcium homeostasis, which leads to oxidative stress and mitochondrial dysfunction.

Original languageEnglish (US)
Pages (from-to)3227-3232
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number6
DOIs
StatePublished - Mar 17 1998
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Amyloid
  • Calcium binding protein
  • Endoplasmic reticulum
  • Mitochondrial transmembrane potential

ASJC Scopus subject areas

  • Genetics
  • General

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