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

• Published in: Neuromolecular medicine 2003, Vol.3 (2), p.119-128
• Main Authors: Pak, Kirk J, Chan, Sic L, Mattson, Mark P
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - toxicity; Animals; Brain - metabolism; Brain - pathology; Brain - physiopathology; Cell Death - drug effects; Cell Death - genetics; Cells, Cultured; Disease Models, Animal; DNA Damage - drug effects; DNA Damage - genetics; Enzyme Inhibitors - pharmacology; Folic Acid Deficiency - genetics; Folic Acid Deficiency - metabolism; Folic Acid Deficiency - physiopathology; Homocysteine - metabolism; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Mutant Strains; Mutation - genetics; Nerve Fibers, Myelinated - metabolism; Nerve Fibers, Myelinated - pathology; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Oligodendroglia - pathology; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases - metabolism; Presenilin-1; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - metabolism; Up-Regulation - drug effects; Up-Regulation - physiology
• ISSN: 1535-1084; 1535-1084
• DOI: 10.1385/NMM:3:2:119

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 beta-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 beta-peptide. Inhibitors of poly (ADP-ribose) polymerase and p53 protected oligodendrocytes against cell death induced by homocysteine and amyloid beta-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.