Vascular-associated neuroinflammation in Alzheimer's disease: differential effects on disease progression modulated by underlying amyloid burden

项目摘要 在占阿尔茨海默病（AD）病例一半以上的可改变因素中， 大多数是血管风险因素（VRF）。鉴于AD患者的数量预计到2040年将翻一番， 这种情况为减少对公共卫生的负面影响提供了一个重要机会。清晰 了解将VRF与AD联系起来的精确的时间和机制变化可能有助于开发 来切断这种联系。因此，本提案的总体目标是阐明 早期血管损伤和随后AD之间联系的潜在靶向机制 病理血管炎症是许多VRF的一个统一特征，这可以诱导或传播 大脑中的神经炎性变化。考虑到神经炎症在AD中的既定作用， 因此，它可能是临床上有用的靶向继发于血管损伤的神经炎性改变。 因此，该提案将检验血管危险因素主要通过增加AD的发病率来促进AD的假设。 神经炎症反应和改变随后的淀粉样蛋白病理学。在这些研究中，我将使用一个很好的- 特征性淀粉样蛋白β（Ab）过表达的AD小鼠模型（APPswe/PS1 dE 9）沿着饮食 高同型半胱氨酸血症（HHcy）模型诱导血管损伤和炎症。在目标1中，我将诱导HHcy 在AD小鼠中，在对应于前驱AD的时期内，以及在Aim 2中，在对应于早期AD的时期内， AD.在这两个目标中，我将在一半的动物中急性治疗血管相关的神经炎症。我会 表征血管损伤和相关神经炎症如何与潜在Ab病理相互作用， 在AD进展的不同阶段产生累加性认知缺陷。此外，这两个目标将包括： 临床相关的神经影像学测量，以将病理改变与可检测的改变联系起来， 脑血流量（动脉自旋标记）和代谢变化（磁共振波谱）。 该项目的成功完成将为VRF和AD之间的联系提供临床相关的见解。 此外，它将提供靶向继发于血管的神经炎症的效用的概念验证。 作为预防或延缓未来认知能力下降的手段。理想情况下，这种方法有一天会 纳入管理AD风险的全面战略。精心设计的职业发展 还正式制定了一项计划，其中包括参加专业讲习班，定期提交数据， 参加科学会议和提高非技术性科学知识。一位经验丰富 一个资深科学家的指导小组，在一个完善的AD研究机构，确保我将有 最佳的机会成长为一个成功的独立研究者致力于AD治疗的发展。

PROJECT SUMMARY Of the modifiable factors that collectively account for over half of Alzheimer’s disease (AD) cases, the majority are vascular risk factors (VRFs). Given that the number of AD patients is expected to double by 2040, this situation presents an important opportunity to reduce negative impacts on public health. Clearer understanding of the precise temporal and mechanistic alterations linking VRFs to AD may enable development of therapeutic approaches to sever that link. The overall goal of this proposal is therefore to elucidate potentially targetable mechanisms underlying the connection between early vascular damage and subsequent AD pathology. Vascular inflammation is one unifying feature of many VRFs, and this can induce or propagate neuroinflammatory changes in the brain. Considering the established role of neuroinflammation in AD pathogenesis, it may be clinically useful to target neuroinflammatory alterations secondary to vascular insult. This proposal will therefore test the hypothesis that vascular risk factors contribute to AD primarily by increasing neuroinflammatory responses and altering subsequent amyloid pathology. For these studies, I will use a well- characterized amyloid beta (Ab) overexpression mouse model of AD (APPswe/PS1dE9) along with a dietary hyperhomocysteinemia (HHcy) model to induce vascular damage and inflammation. In Aim 1, I will induce HHcy in AD mice within a period corresponding to prodromal AD, and in Aim 2 within a period corresponding to early AD. In both aims l will acutely treat the vascular-associated neuroinflammation in half of the animals. I will characterize how vascular damage and associated neuroinflammation interact with underlying Ab pathology to produce additive cognitive deficits at different stages of AD progression. In addition, both aims will include clinically relevant neuroimaging measures to connect pathological alterations with detectable alterations in cerebral blood flow (arterial spin labeling) and metabolic changes (magnetic resonance spectroscopy). Successful completion of this project will provide clinically-relevant insight into the links between VRFs and AD. Further, it will provide proof-of-concept of the utility of targeting neuroinflammation secondary to vascular damage as a means of preventing or delaying future cognitive decline. Ideally, such an approach will someday be incorporated into a comprehensive strategy of managing AD risk. A carefully designed career development plan has also been formalized that includes participation in specialty workshops, regular presentation of data, participation in scientific meetings and enhancement of non-technical science proficiencies. An experienced mentoring group of senior scientists, in a well-established institution for AD research, ensure that I will have optimal opportunity to grow into a successful independent investigator devoted to AD therapeutic development.