Early Oligodendrocyte/Myelin Pathology in Alzheimer's Disease Mice Constitutes a Novel Therapeutic Target
Early Oligodendrocyte/Myelin Pathology in Alzheimer's Disease Mice Constitutes a Novel Therapeutic Target
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DOI：
10.2353/ajpath.2010.100087
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发表时间：
2010-09-01
影响因子：
6
通讯作者：
Bowers, William J.
中科院分区：
文献类型：
--
作者：
Desai, Maya K.;Mastrangelo, Michael A.;Bowers, William J.
在阿尔茨海默氏病（AD）影响的大脑中检测到髓鞘破坏，提出了少突胶质细胞在这种神经退行性疾病的长期过程中经历病理生理攻击的可能性。由病理性淀粉样蛋白β肽和/或通过来自退化神经元的信号引起的直接毒性作用引起的少突胶质细胞损害在疾病过程中可能起重要作用。我们先前证明了3 x Tg-AD小鼠，其携带人淀粉样蛋白前体蛋白瑞典突变转基因、早老素敲入突变和tau P301 L突变转基因，在淀粉样蛋白和tau病理出现之前的时间点，表现出总体髓鞘形成模式和少突胶质细胞状态的显著改变。在此，我们证明，所有导致增加caspase-3的表达和凋亡细胞死亡的未分化和分化的小鼠少突胶质细胞前体（mOP）细胞在体外。通过使用表达A β（1-42）特异性细胞内抗体（胞内抗体）的重组腺相关病毒血清型-2（rAAV 2）载体，在3 x Tg-AD小鼠的载体输注的脑区域中恢复了少突胶质细胞和髓鞘标志物表达以及髓鞘完整性。总的来说，这项工作提供了进一步的见解A β（1-42）介导的毒性的影响，在AD的早期症状前阶段的微妙髓鞘破坏的时间和空间进展，并可能有助于验证新的治疗方案，旨在避免这些早期损伤。(Am J Pathol 2010 177：1422-1435; DOI：10.2353/ajpath.2010.100087）
The detection of myelin disruptions in Alzheimer's disease (AD) affected brain raises the possibility that oligodendrocytes undergo pathophysiological assault over the protracted course of this neurodegenerative disease. Oligodendrocyte compromise arising from direct toxic effects imparted by pathological amyloid-beta peptides and/or through signals derived from degenerating neurons could play an important role in the disease process. We previously demonstrated that 3 x Tg-AD mice, which harbor the human amyloid precursor protein Swedish mutant transgene, presenilin knock-in mutation, and tau P301L mutant transgene, exhibit significant alterations in overall myelination patterns and oligodendrocyte status at time points preceding the appearance of amyloid and tau pathology. Herein, we demonstrate that All leads to increased caspase-3 expression and apoptotic cell death of both nondifferentiated and differentiated mouse oligodendrocyte precursor (mOP) cells in vitro. Through use of a recombinant adeno-associated virus serotype-2 (rAAV2) vector expressing an A beta(1-42)-spechic intracellular antibody (intrabody), oligodendrocyte and myelin marker expression, as well as myelin integrity, were restored in the vector-infused brain regions of 3 x Tg-AD mice. Overall, this work provides further insights into the impact of A beta(1-42)-mediated toxicity on the temporal and spatial progression of subtle myelin disruption during the early presymptomatic stages of AD and may help to validate new therapeutic options designed to avert these early impairments. (Am J Pathol 2010 177:1422-1435; DOI: 10.2353/ajpath.2010.100087)