Presenilin-1 mutation sensitizes oligodendrocytes to glutamate and amyloid toxicities, and exacerbates white matter damage and memory impairment in mice

Kirk Pak, Sic L. Chan, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

Damage to white matter occurs in the brains of patients with Alzheimer's disease (AD), but it is not known if and how oligodendrocytes are affected in AD, nor whether white matter alterations contribute to the cognitive dysfunction in this disease. Mutations in the gene encoding presenilin-1 (PS1) cause some cases of early-onset inherited AD. These mutations may promote neuronal degeneration by increasing the production of neurotoxic forms of amyloid β-peptide and by perturbing cellular calcium homeostasis. Damage to oligodendrocytes induced by a demyelinating agent is enhanced, and spatial learning is impaired in PS1 mutant knockin mice. Oligodendrocytes from PS1 mutant knockin mice are more vulnerable to being killed by glutamate and amyloid β-peptide, and exhibit an abnormality in calcium regulation which is responsible for their death. These findings demonstrate an adverse effect of a disease-causing PS1 mutation in oligodendrocytes, and suggest a mechanism responsible for white matter damage in AD and a contribution of such damage to cognitive impairment.

Original languageEnglish (US)
Pages (from-to)53-64
Number of pages12
JournalNeuroMolecular Medicine
Volume3
Issue number1
DOIs
StatePublished - 2003

Fingerprint

Presenilin-1
Oligodendroglia
Amyloid
Glutamic Acid
Alzheimer Disease
Mutation
Calcium
Peptides
Homeostasis
White Matter
Brain
Genes
Cognitive Dysfunction

Keywords

  • Alzheimer's disease
  • Amyloid beta-peptide
  • Apoptosis
  • Axons
  • Calcium
  • Cognitive
  • Excitotoxicity
  • White matter

ASJC Scopus subject areas

  • Neuroscience(all)
  • Genetics
  • Cell Biology

Cite this

Presenilin-1 mutation sensitizes oligodendrocytes to glutamate and amyloid toxicities, and exacerbates white matter damage and memory impairment in mice. / Pak, Kirk; Chan, Sic L.; Mattson, Mark P.

In: NeuroMolecular Medicine, Vol. 3, No. 1, 2003, p. 53-64.

Research output: Contribution to journalArticle

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