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 journalArticle

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

Fingerprint

Presenilin-1
Synaptosomes
Homeostasis
Amyloid
Calcium
Mutation
Peptides
Alzheimer Disease
Chromosomes, Human, Pair 14
Caspases
Endoplasmic Reticulum
Synapses
Transgenic Mice
Chromosomes
Buffers
Genes
Chemical activation
mouse presenilin 1

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice. / Begley, James G.; Duan, Wenzhen; Chan, Sic; Duff, Karen; Mattson, Mark P.

In: Journal of Neurochemistry, Vol. 72, No. 3, 1999, p. 1030-1039.

Research output: Contribution to journalArticle

Begley, James G. ; Duan, Wenzhen ; Chan, Sic ; Duff, Karen ; Mattson, Mark P. / Altered calcium homeostasis and mitochondrial dysfunction in cortical synaptic compartments of presenilin-1 mutant mice. In: Journal of Neurochemistry. 1999 ; Vol. 72, No. 3. pp. 1030-1039.
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