Presenilin-1 mutation sensitizes oligodendrocytes to glutamate and amyloid toxicities, and exacerbates white matter damage and memory impairment in mice.
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 beta-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 beta-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.
Pak
Kirk
K
Laboratory of Neurosciences, National Institute of Aging Gerontology Reseasrch Center, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
Chan
Sic L
SL
Mattson
Mark P
MP
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020013:Calcium Signaling / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism / Q000633:toxicity; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008569:Memory Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics*; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity; D053764:Presenilin-1
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid