An Alzheimer's disease-relevant presenilin-1 mutation augments amyloid-beta-induced oligodendrocyte dysfunction.
An Alzheimer's disease-relevant presenilin-1 mutation augments amyloid-beta-induced oligodendrocyte dysfunction.
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DOI：
10.1002/glia.21131
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发表时间：
2011-04
期刊：
影响因子：
6.2
通讯作者：
Bowers, William J.
中科院分区：
文献类型：
--
作者：
Desai, Maya K.;Guercio, Brendan J.;Narrow, Wade C.;Bowers, William J.
白色物质病理学已经在家族性阿尔茨海默病（FAD）-折磨个体的脑中在AD的症状前和临床前阶段被记录。髓鞘形成完整性的这些缺陷是如何产生的，以及它们在AD病理生理学中可能发挥的作用尚未完全阐明。我们先前证明，携带人淀粉样蛋白前体Swedish突变、早老素-1 M146 V（PS1 M146 V）敲入突变和tauP 301 L突变的三重转基因AD（3xTg-AD）小鼠表现出与FAD患者类似的髓鞘异常，并且Aβ1-42导致这些白色缺陷。在此，我们证明了PS1 M146 V突变使小鼠少突胶质前体细胞（mOP）在体外易于发生Aβ1-42诱导的细胞分化改变。此外，PS1 M146 V表达损害mOP细胞功能和MBP蛋白分布，这一过程在暴露于Aβ1-42时进一步恶化。我们发现，PS1 M146 V和Aβ1-42引发的髓鞘形成缺陷和MBP亚细胞错误定位可以通过GSK-3β抑制剂TWS 119治疗有效预防，从而暗示GSK-3β激酶活性在该致病级联反应中。总体而言，这项工作提供了进一步的机制洞察PS1 M146 V和Aβ1-42驱动的少突胶质细胞功能障碍和髓鞘损伤在早期症状前阶段的AD，并提供了一个新的目标，在少突胶质细胞开发治疗，旨在避免AD相关的白色物质病理。
White matter pathology has been documented in the brains of familial Alzheimer’s disease (FAD)-afflicted individuals during pre-symptomatic and pre-clinical 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 pre-symptomatic stages of AD, and provides a new target in oligodendrocytes for developing therapies designed to avert AD-related white matter pathology.
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影响因子：
6
作者：
Desai, Maya K.;Mastrangelo, Michael A.;Bowers, William J.
通讯作者：
Bowers, William J.
影响因子：
4.4
作者：
Hanyu, H;Sakurai, H;Abe, K
通讯作者：
Abe, K
DOI：
10.1073/pnas.92.22.10369
发表时间：
1995-10-24
影响因子：
11.1
作者：
LOPRESTI, P;SZUCHET, S;BINDER, LI
通讯作者：
BINDER, LI
影响因子：
2.6
作者：
Dickerson, Bradford C.;Sperling, Reisa A.
通讯作者：
Sperling, Reisa A.
DOI：
10.1083/jcb.123.2.431
发表时间：
1993-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Ainger K;Avossa D;Morgan F;Hill SJ;Barry C;Barbarese E;Carson JH
通讯作者：
Carson JH