An Alzheimer's Disease-Relevant Presenilin-1 Mutation Augments Amyloid-Beta-Induced Oligodendrocyte Dysfunction

研究表明,家族性阿尔茨海默病(FAD)患者处于无症状或临床前阶段时,脑白质即出现病理改变。此种改变在髓鞘破坏及阿尔茨海默病(AD)病理生理中的作用有待进一步研究阐明。笔者前期研究证实,三重转基因AD小鼠(人淀粉前体蛋白基因的Swedish突变,早老素-1 M146V(PS1M146V)敲入突变及tauP301L突变)表现出类似FAD患者的髓鞘破坏,Aβ1-42促进了白质病变。本研究离体实验证实,PS1M146V变异导致小鼠少突胶质前体细胞在分化过程中易出现类似Aβ1-42诱导的变化。PS1M146V的表达损伤少突胶质前体细胞的功能并影响髓鞘碱性蛋白的分布,暴露于Aβ1-42加重此影响。由PS1M146V及Aβ1-42导致的髓鞘破坏及髓鞘碱性蛋白在亚细胞结构中的误定位可被TWS119(糖原合成激酶(GSK)-3β抑制剂)抑制,提示GSK-3β激酶活动在此病理过程中有重要作用。综上所述,本研究有助于增加对AD早期无症状阶段,由PS1M146V及Aβ1-42导致少突胶质细胞功能异常及髓鞘损伤的机制的理解,并提供了针对少突胶质细胞预防AD相关白质病变的新的治疗靶点。

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.