神经损伤与功能重建2011，Vol.6Issue(2)：128-141,14.
An Alzheimer's Disease-Relevant Presenilin-1Mutation Augments Amyloid-Beta-Induced Oligodendrocyte Dysfunction
An Alzheimer's Disease-Relevant Presenilin-1 Mutation Augments Amyloid-Beta-Induced Oligodendrocyte Dysfunction
MAYA K. DESAI 1BRENDAN J. GUERCIO 1WADE C. NARROW 1AND WILLIAM J. BOWERS1
作者信息
摘要
Abstract
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 (PS1M146V) knock-in mutation, and tauP301L mutation, exhibit myelin abnormalities analogous to FAD patients and that Aβ1-42 contributes to these white matter deficits. Herein, we demonstrate that the PS1M146V mutation predisposes mouse oligodendrocyte precursor (mOP) cells to Aβ1 42-induced alterations in cell differentiation in vitro. Furthermore, PS1M146V expression compromised mOP cell function and MBP protein distribution, a process that is further aggravated with exposure to Aβ1-42. We found that the myelination defect and MBP subcellular mislocalization triggered by PS1M146V and Aβ1 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 PS1M146V and Aβ1-42-driven oligodendrocyte dysfunction and myelin 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.关键词
阿尔茨海默病/白质/髓磷脂/少突胶质细胞/髓鞘碱性蛋白/淀粉β样蛋白/早老素-1/3重转基因ADKey words
Alzheimer's disease/ white matter/ myelin/ oligodendrocyte/ MBP/ amyloid beta/ presenilin-1/ 3xTg-AD分类
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MAYA K. DESAI,BRENDAN J. GUERCIO,WADE C. NARROW,AND WILLIAM J. BOWERS..An Alzheimer's Disease-Relevant Presenilin-1Mutation Augments Amyloid-Beta-Induced Oligodendrocyte Dysfunction[J].神经损伤与功能重建,2011,6(2):128-141,14.
