Homocysteine and folate deficiency sensitize oligodendrocytes to the cell death-promoting effects of a presenilin-1 mutation and amyloid β-peptide

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

Research output: Contribution to journalArticle

Abstract

Although damage to white matter occurs in the brains of patients with Alzheimer's disease (AD), the underlying mechanisms are unknown. Recent findings suggest that individuals with elevated levels of homocysteine are at increased risk of AD. Here we show that oligodendrocytes from mice expressing a mutant form of presenilin-1 (PS1) that causes familial AD exhibit increased sensitivity to death induced by homocysteine compared to oligodendrocytes from wild-type control mice. Homocysteine also sensitized oligodendrocytes to the cytotoxicity of amyloid β-peptide. Folate deficiency, which is known to result in elevated levels of homocysteine in vivo, also sensitized oligodendrocytes to the cell-death-promoting actions of mutant PS1 and amyloid β-peptide. Inhibitors of poly (ADP-ribose) polymerase and p53 protected oligodendrocytes against cell death induced by homocysteine and amyloid β-peptide, consistent with a role for a DNA-damage response in the cell death process. These findings demonstrate an adverse effect of homocysteine on oligodendrocytes, and suggest roles for homocysteine and folate deficiency in the white matter damage in AD and related neurodegenerative disorders.

Original languageEnglish (US)
Pages (from-to)119-127
Number of pages9
JournalNeuroMolecular Medicine
Volume3
Issue number2
DOIs
StatePublished - 2003
Externally publishedYes

Fingerprint

Presenilin-1
Oligodendroglia
Homocysteine
Folic Acid
Amyloid
Cell Death
Peptides
Mutation
Alzheimer Disease
Neurodegenerative Diseases
DNA Damage
Brain

Keywords

  • Alzheimer's disease
  • Apoptosis
  • Folic acid
  • P53 tumor suppressor
  • PARP
  • Stroke
  • White matter

ASJC Scopus subject areas

  • Neuroscience(all)
  • Genetics
  • Cell Biology

Cite this

Homocysteine and folate deficiency sensitize oligodendrocytes to the cell death-promoting effects of a presenilin-1 mutation and amyloid β-peptide. / Pak, Kirk J.; Chan, Sic L.; Mattson, Mark P.

In: NeuroMolecular Medicine, Vol. 3, No. 2, 2003, p. 119-127.

Research output: Contribution to journalArticle

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