Investigation of Dysfunctional Myelin Repair in Alzheimer's Disease

项目摘要 阿尔茨海默病（AD）是痴呆症最常见的形式，其疾病机制在 除了淀粉样蛋白和tau蛋白之外的AD还没有很好的定义。髓鞘完整性是AD研究中的一个未充分研究的领域， 目前尚不清楚为什么所有老年人中发生的髓鞘损伤会加重为病理性损伤。 在AD患者中，在淀粉样蛋白阳性的临床前AD中已经证明了髓鞘数量的减少 患者，这可能是一个独立的过程，从灰质变性中看到的临床前和前驱 疾病最近的文献表明，少突胶质细胞祖细胞（OPC），分化为 少突胶质细胞和促进髓鞘维持和修复的神经胶质细胞在AD中是功能失调的。小胶质细胞是 也已知有助于髓磷脂的维护和修复，特别是通过最近表征的神经胶质， 小胶质细胞衍生的转氨酶-2交联酶（TG 2）下游的to-胶质细胞信号传导途径， 其通过G-偶联蛋白受体促进OPC增殖并因此促进髓鞘形成。尽管文献 暗示AD中髓鞘修复受损，尚未研究该途径与当前AD的关系 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， 修复髓鞘，并在脱髓鞘的动物模型中提供显著的治疗效果。的 该提案的总体目标是探索髓鞘修复的潜在机制， AD中的白色物质变性、修复和疾病进展。在目标1中，我将分析五种基因的变异， 候选髓鞘修复基因，OLIG 1、OLIG 2、SOX 10、SOX 17和MBP，其已被选择，因为 广泛的文献支持它们在髓鞘修复中的作用，迄今为止在AD中相对缺乏评估。在目标2中 我将分析mRNA表达水平，以了解这些变体的功能。最后，在目标3中，我将 研究可能负责抑制的候选途径的基因变体和mRNA表达 髓鞘修复本项目将测试两个假设：1）遗传变异（SNP）和mRNA表达， 选定的髓鞘修复基因将与AD的异常成像和临床生物标志物两者相关;以及， 2)上游小胶质细胞源性TG 2-ADGRG 1的遗传变异（SNPS）和异常mRNA表达 在髓鞘修复中重要的信号通路将与异常的成像和临床生物标志物相关 的AD。该项目将使用AD患者的神经成像和遗传数据， 来自AD神经影像学倡议（ADNI）和印第安纳州记忆和衰老研究（IMAS）队列， 美国国家情报局指定的印第安纳州反种族歧视委员会。它还将使我能够跟踪相关的临床医生，并促进以下方面的培训： 成像，遗传学和相关的神经生物学必要的提交一个新的和翻译博士 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.