Involvement of myelin integrity in Alzheimer's disease pathogenesis

描述（由申请人提供）：此K99/R00申请提供职业发展培训和研究计划，以进一步了解阿尔茨海默病（AD）背景下白质中的胶质反应。待验证的假设是，阿尔茨海默病发生髓磷脂完整性的进行性丧失，激活小胶质细胞走向促炎前反馈回路，介导微管相关蛋白tau的过度磷酸化和传统的阿尔茨海默病病理：神经性斑块（NP）和神经原纤维缠结（nft）。阿尔茨海默病通常被认为是一种中枢神经系统灰质疾病，但它也有明显的脑白质进行性恶化。最近的证据表明，髓磷脂完整性的改变可能是驱动AD病理的早期因素，通过刺激炎性小胶质细胞激活和随后的轴突损伤。我们已经做了大量的工作来了解阿尔茨海默氏症灰质中的胶质细胞反应，但对阿尔茨海默氏症白质中的小胶质细胞激活知之甚少，尽管我们和其他人已经发现阿尔茨海默氏症白质中的小胶质细胞激活和炎症反应比灰质更强烈。没有研究系统地和定量地检查髓磷脂变化和炎症谱作为疾病进展的功能。我们的项目将通过使用人体解剖组织和显示髓磷脂完整性丧失的小鼠模型来测试我们的假设来填补这一空白。我们的具体目标是：1)量化髓磷脂完整性，小胶质细胞激活，

DESCRIPTION (provided by applicant): This K99/R00 application provides career development training and a research plan to further the understanding of glial responses in white matter in the context of Alzheimer's disease (AD). The hypothesis to be tested is that a progressive loss of myelin integrity occurs in AD, activating microglia towards a proinflammatory feed-forward loop, which mediates hyperphosphorylation of the microtubule-associated protein tau and traditional AD pathology: neuritic plaques (NP) and neurofibrillary tangles (NFTs). Conventionally considered a disease of the CNS gray matter, AD also has pronounced and progressive deterioration of cerebral white matter. Recent evidence suggests that changes in myelin integrity could be an early factor driving AD pathology, through stimulation of inflammatory microglia activation and subsequent axonal damage. Extensive work has been done to understand the glial response in AD gray matter yet very little is known about microglia activation in AD white matter, despite the fact that we and others have found a more robust activation of microglia and inflammatory response in AD white matter compared to gray matter. No studies have systematically and quantitatively examined myelin changes and inflammatory profiles as a function of disease progression. Our project will fill this gap by using human autopsy tissue and a mouse model that exhibits loss of myelin integrity to test our hypothesis. Our specific aims are: 1) Quantify the relationship between myelin integrity, microglia activation, proinflammatory cytokine levels, and traditional measures of AD burden (NPs and NFTs) in the white matter of autopsy samples; 2) Determine if loss of myelin integrity, induced by mutation in PLP, in hTau mice will accelerate hyper-phosphorylated tau pathology, and if this pathology can be rescued by suppressing the chronic neuroinflammation using a glia cytokine inhibitor. This project takes advantage of a strong scientific environment and extensive resources at the University of Kentucky, including the Alzheimer's Disease Center, clinically well-characterized autopsy cases that span the disease pathology continuum, and renowned scientific expertise of an enthusiastic and committed mentoring team. A comprehensive training and career development plan has been developed for the K99 phase that includes further scientific training in oligodendrocyte/myelin biology and human neuropathology; formal coursework and participation in local, national and international scientific meetings; evaluative meetings with th mentoring team; and activities designed to improve communication, writing, teaching, and management skills. Overall, there is an outstanding intellectual environment and access to relevant expertise in the applicant's project area, multiple opportunities for career growth, and substantial institutional commitment. This rich and supportive environment will enable a highly promising young scientist to further develop his research expertise, pursue his structured training and career development plan, and launch his career as an independent academic investigator.