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An Alzheimer's disease‐relevant presenilin‐1 mutation augments amyloid‐beta‐induced oligodendrocyte dysfunction
Author(s) -
Desai Maya K.,
Guercio Brendan J.,
Narrow Wade C.,
Bowers William J.
Publication year - 2011
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.21131
Subject(s) - presenilin , oligodendrocyte , biology , mutation , white matter , amyloid beta , amyloid precursor protein , genetically modified mouse , myelin , transgene , amyloid (mycology) , microglia , neuroscience , alzheimer's disease , microbiology and biotechnology , immunology , disease , pathology , genetics , inflammation , medicine , central nervous system , biochemistry , gene , peptide , botany , radiology , magnetic resonance imaging
White matter pathology has been documented in the brains of familial Alzheimer's disease (FAD)‐afflicted individuals during presymptomatic and preclinical stages of AD. How these defects in myelination integrity arise and what roles they may play in AD pathophysiology have yet to be fully elucidated. We previously demonstrated that triple‐transgenic AD (3xTg‐AD) mice, which harbor the human amyloid precursor Swedish mutation, presenilin‐1 M146V (PS1 M146V ) knock‐in mutation, and tau P301L mutation, exhibit myelin abnormalities analogous to FAD patients and that Aβ 1‐42 contributes to these white matter deficits. Herein, we demonstrate that the PS1 M146V mutation predisposes mouse oligodendrocyte precursor (mOP) cells to Aβ 1‐42 ‐induced alterations in cell differentiation in vitro . Furthermore, PS1 M146V expression compromised mOP cell function and MBP protein distribution, a process that is further aggravated with exposure to Aβ 1‐42 . We found that the myelination defect and MBP subcellular mislocalization triggered by PS1 M146V and Aβ 1‐42 can be effectively prevented by treatment with the GSK‐3β inhibitor, TWS119, thereby implicating GSK‐3β kinase activity in this pathogenic cascade. Overall, this work provides further mechanistic insights into PS1 M146V and Aβ 1‐42 ‐driven oligodendrocyte dysfunction andmyelin damage during early presymptomatic stages of AD, and provides a new target in oligodendrocytes for developing therapies designed to avert AD‐related white matter pathology. © 2011 Wiley‐Liss, Inc.