Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice

James G. Begley, Wenzhen Duan, Sic Chan, Karen Duff, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer's disease is characterized by amyloid β-peptide deposition, synapse loss, and neuronal death, which are correlated with cognitive impairments. Mutations in the presenilin-1 gene on chromosome 14 are causally linked to many cases of early-onset inherited Alzheimer's disease. We report that synaptosomes prepared from transgenic mice harboring presenilin-1 mutations exhibit enhanced elevations of cytoplasmic calcium levels following exposure to depolarizing agents, amyloid β-peptide, and a mitochondrial toxin compared with synaptosomes from nontransgenic mice and mice overexpressing wild-type presenilin-1. Mitochondrial dysfunction and caspase activation following exposures to amyloid β-peptide and metabolic insults were exacerbated in synaptosomes from presenilin-1 mutant mice. Agents that buffer cytoplasmic calcium or that prevent calcium release from the endoplasmic reticulum protected synaptosomes against the adverse effect of presenilin-1 mutations on mitochondrial function. Abnormal synaptic calcium homeostasis and mitochondrial dysfunction may contribute to the pathogenic mechanism of presenilin-1 mutations.

Original languageEnglish (US)
Pages (from-to)1030-1039
Number of pages10
JournalJournal of Neurochemistry
Volume72
Issue number3
DOIs
StatePublished - 1999
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Amyloid
  • Apoptosis
  • Caspase
  • Depolarization
  • Reactive oxygen species
  • Synaptosomes

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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