Amyloid β1-42 oligomer inhibits myelin sheet formation in vitro.
Accumulating evidence indicates that white matter degeneration contributes to the neural disconnections that underlie Alzheimer's disease pathophysiology. Although this white matter degeneration is partly attributable to axonopathy associated with neuronal degeneration, amyloid β (Aβ) protein-mediated damage to oligodendrocytes could be another mechanism. To test this hypothesis, we studied effects of soluble Aβ in oligomeric form on survival and differentiation of cells of the oligodendroglial lineage using highly purified oligodendroglial cultures from rats at different developmental stages. Aβ oligomer at 10 μM or higher reduced survival of mature oligodendrocytes, whereas oligodendroglial progenitor cells (OPCs) were relatively resistant to the Aβ oligomer-mediated cytotoxicity. Further study revealed that Aβ oligomer even at 1 μM accelerated 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) formazan exocytosis in mature oligodendrocytes, and, more significantly, inhibited myelin sheet formation after induction of in vitro differentiation of OPCs. These results imply a novel pathogenetic mechanism underlying Aβ oligomer-mediated white matter degeneration, which could impair myelin maintenance and remyelination by adult OPCs, resulting in accumulating damage to myelinating axons thereby contributing to neural disconnections.
Horiuchi
Makoto
M
Department of Neurology, University of California Davis, School of Medicine, Sacramento, CA 95817, United States.
Maezawa
Izumi
I
Itoh
Aki
A
Wakayama
Kouji
K
Jin
Lee-Way
LW
Itoh
Takayuki
T
Decarli
Charles
C
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology*; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity*; D061251:Primary Cell Culture; D051381:Rats; D011917:Rats, Inbred Lew; D013234:Stem Cells / Q000187:drug effects* / Q000473:pathology; D014407:Tumor Cells, Cultured; D014855:Wallerian Degeneration / Q000378:metabolism* / Q000473:pathology
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)