Investigation of Dysfunctional Myelin Repair in Alzheimer's Disease

项目总结 阿尔茨海默病(AD)是最常见的痴呆症形式，其发病机制在 淀粉样蛋白以外的AD和tau没有很好的定义。髓鞘完整性是AD研究中一个未被充分研究的领域，它 目前尚不清楚为什么在所有老年人中发生的髓鞘损伤会加剧为一种病理 阿尔茨海默病患者的数量。淀粉样蛋白阳性的临床前AD患者髓鞘数量减少 患者，这可能是一个与临床前和前驱症状所见的灰质变性分开的过程 疾病。最近的文献表明，少突胶质前体细胞(OPC)分化为 少突胶质细胞和促进髓鞘的维持和修复，在AD时功能失调。小胶质细胞是 也已知有助于髓鞘的维持和修复，特别是通过最近表征的胶质细胞- 小胶质细胞来源的谷氨酰胺转氨酶-2交联酶(TG2)下游的TO-胶质细胞信号通路， 它通过G偶联蛋白受体促进OPC的增殖，从而促进髓鞘形成。虽然文学作品 阿尔茨海默病与髓鞘修复受损有关这一途径与当前阿尔茨海默病的关系尚未被研究 生物标志物。值得注意的是，乙酰胆碱酯酶抑制剂多奈哌齐促进少突胶质细胞分化和 修复髓鞘，并在脱髓鞘动物模型中提供显著的治疗效果。这个 这项建议的主要目标是探索髓鞘修复作为驱动因素的潜在机制。 阿尔茨海默病中的白质变性、修复和疾病进展。在目标1中，我将分析五个基因变异 候选髓鞘修复基因，OLIG1，OLIG2，SOX10，SOX17和MBP，已被选择，因为 广泛的文献支持它们在髓鞘修复中的作用，但到目前为止在AD中相对缺乏评估。在AIM 2 我将分析mRNA的表达水平，以了解这些变体的功能。最后，在《目标3》中我将 研究可能导致抑制的候选途径的基因变异和mRNA表达 髓鞘修复。本项目将检验两个假说：1)遗传变异(SNPs)和基因表达 选定的髓鞘修复基因将与AD的异常影像和临床生物标记物相关； 2)上游小胶质细胞来源的TG2-ADGRG1的遗传变异(SNPs)和异常mRNA表达 信号通路，在髓鞘修复中的重要作用，将与异常的影像和临床生物标志物相关 公元一代的。该项目将使用整个AD患者的神经成像和遗传数据，利用数据 来自AD神经成像倡议(ADNI)和印第安纳州记忆和老龄化研究(IMAS)队列，紧随其后的是 NIA指定的印第安纳州ADRC。它还将使我能够跟踪相关临床医生，并促进培训 影像、遗传学和相关神经生物学是提交新书和翻译博士所必需的 论文。

PROJECT SUMMARY Alzheimer’s disease (AD) is the most common form of dementia, and disease mechanisms important in AD beyond amyloid and tau are not well defined. Myelin integrity is an understudied field in AD research and it is currently not well understood why myelin injury that occurs in all aging adults is exacerbated to a pathologic amount in those with AD. Decreased myelin quantity has been demonstrated in amyloid-positive preclinical AD patients, which may be a separate process from gray matter degeneration seen in preclinical and prodromal disease. Recent literature suggests that oligodendrocyte progenitor cells (OPC), which differentiate into oligodendrocytes and promote myelin sheath maintenance and repair, are dysfunctional in AD. Microglia are also known to contribute to myelin maintenance and repair specifically through the recently characterized glia- to-glia signaling pathway downstream of microglia-derived transglutaminase-2 cross-linking enzyme (TG2), which promotes OPC proliferation and thus myelination via g-coupled protein receptors. Although the literature implicates impaired myelin repair in AD this pathway has not been investigated in relation to current AD biomarkers. Of note, the acetylcholinesterase inhibitor donepezil promotes oligodendrocyte differentiation and repair of the myelin sheath and provides significant therapeutic effect in animal models of demyelination. The overarching objective of this proposal is to explore underlying mechanisms of myelin repair as drivers of white matter degeneration, repair, and disease progression in AD. In Aim 1, I will analyze gene variants of five candidate myelin repair genes, OLIG1, OLIG2, SOX10, SOX17, and MBP, which have been chosen due to extensive literature support of their role in myelin repair and relative lack of assessment in AD to date. In Aim 2 I will analyze mRNA expression levels to understand functionality of these variants. Finally, in Aim 3 I will investigate gene variants and mRNA expression of a candidate pathway that may be responsible for inhibited myelin repair. This project will test two hypotheses: 1) genetic variations (SNPs) and mRNA expression of selected myelin repair genes will be associated with both abnormal imaging and clinical biomarkers of AD; and, 2) genetic variations (SNPS) and abnormal mRNA expression of the upstream microglia-derived TG2-ADGRG1 signaling pathway, important in myelin repair, will be associated with abnormal imaging and clinical biomarkers of AD. The project will use neuroimaging and genetic data in patients across the AD continuum, utilizing data from the AD Neuroimaging Initiative (ADNI) and Indiana Memory and Aging Study (IMAS) cohort followed by the NIA-designated Indiana ADRC. It will also allow me to shadow relevant clinicians as well as facilitate training in imaging, genetics, and relevant neurobiology necessary to submission of a novel and translational doctoral thesis.