Involvement of myelin integrity in Alzheimer's disease pathogenesis

描述(由申请人提供)：这份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)背景下白质中的神经胶质反应。需要检验的假设是，AD发生髓鞘完整性的进行性丧失，激活小胶质细胞进入促炎前馈环，该环介导微管相关蛋白tau的过度磷酸化和传统的AD病理：神经性斑块(NP)和神经原纤维缠结(NFTs)。阿尔茨海默病通常被认为是一种中枢神经系统灰质疾病，也有明显的脑白质进行性恶化。最近的证据表明，髓鞘完整性的改变可能是导致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。人们已经做了大量的工作来了解AD灰质中的胶质反应，但对AD白质中小胶质细胞的激活知之甚少，尽管我们和其他人已经发现，与灰质相比，AD白质中的小胶质细胞激活和炎症反应更强烈。还没有研究系统地和定量地检查髓鞘变化和炎症特征作为疾病进展的函数。我们的项目将通过使用人类尸检组织和表现出髓鞘完整性丧失的小鼠模型来填补这一空白，以检验我们的假设。我们的具体目标是：1)量化髓鞘完整性、小胶质细胞激活、 (2)确定由PLP突变导致的hTau小鼠髓鞘完整性的丧失是否会加速过度磷酸化的tau病理，以及是否可以通过使用胶质细胞因子抑制剂抑制慢性神经炎症来挽救这种病理。这个项目利用了肯塔基大学强大的科学环境和广泛的资源，包括阿尔茨海默氏症中心，跨越疾病病理连续的临床特征良好的尸检病例，以及热情和忠诚的指导团队的著名科学专业知识。已经为K99阶段制定了全面的培训和职业发展计划，其中包括进一步的少突胶质细胞/髓鞘生物学和人类神经病理学的科学培训；正式的课程作业和参加地方、国家和国际科学会议；与指导小组的评价性会议；以及旨在改善沟通、写作、教学和管理技能的活动。总体而言，在申请人的项目领域，有一个出色的智力环境和获得相关专业知识的机会，职业发展的多种机会，以及大量的机构承诺。这种丰富和支持的环境将使一名非常有前途的年轻科学家进一步发展他的研究专长，追求他的有系统的培训和职业发展计划，并开始他的独立学术研究人员的职业生涯。

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.