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

阿尔茨海默病中的血管相关神经炎症：潜在淀粉样蛋白负荷调节对疾病进展的不同影响

• 批准号: 9469994
• 负责人: David James Braun
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9469994
• 关键词: Abeta synthesis; Acute; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloid deposition; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Blood - brain barrier anatomy; Blood Vessels; Brain; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Clinical; Cognitive; Cognitive deficits; Data; Deposition; Development Plans; Diet; Disease Progression; Educational workshop; Ensure; Functional disorder; Future; Goals; Hyperhomocysteinemia; Hypertension; Impaired cognition; Inflammation; Inflammatory; Injury; Institution; Link; Magnetic Resonance Spectroscopy; Measures; Mediating; Memory impairment; Mentors; Metabolic; Modeling; Mus; Neuroglia; Obesity; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Pattern; Pharmaceutical Preparations; Process; Public Health; Research; Research Personnel; Risk; Risk Factors; Role; Science; Secondary to; Senior Scientist; Spin Labels; Testing; Training; Translating; Vascular Diseases; abeta accumulation; abeta deposition; amyloid pathology; beta amyloid pathology; brain metabolism; career development; cerebral hypoperfusion; clinically relevant; comorbidity; cytokine; design; epidemiology study; experience; glial activation; hypercholesterolemia; inflammatory marker; insight; medical specialties; meetings; middle age; modifiable risk; mouse model; neuroimaging; neuroinflammation; overexpression; prevent; response; stem; therapeutic development; tool; treatment strategy; vascular inflammation

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.

项目总结 在总共占阿尔茨海默病(AD)病例一半以上的可改变因素中， 大多数是血管危险因素(VRF)。鉴于预计到2040年阿尔茨海默病患者数量将翻一番， 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。更清晰 了解将VRF与AD联系起来的精确的时间和机械变化可能会使开发成为可能 来切断这种联系的治疗方法。因此，这项提案的总体目标是阐明潜在的 早期血管损伤与随后的AD之间联系的靶向机制 病理学。血管炎症是许多VRF的一个统一特征，可以诱发或传播。 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 在发病机制上，针对血管损伤继发的神经炎性改变可能在临床上有用。 因此，这项提议将检验血管风险因素主要通过增加 神经炎性反应和改变随后的淀粉样蛋白病理。对于这些研究，我将使用一口井- AD小鼠模型(APPswe/PS1dE9)淀粉样β蛋白(Ab)高表达的特征及饮食 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，在与前驱AD相对应的时期内，在目标2中，在与早期相对应的时期内 广告。在这两个目标中，L将尖锐地治疗一半动物的血管相关神经炎。这就做 描述血管损伤和相关的神经炎症如何与潜在的抗体病理相互作用 在阿尔茨海默病进展的不同阶段产生累加性认知缺陷。此外，这两个目标都将包括 临床相关的神经成像措施，将病理改变与可检测到的改变联系起来 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洞察。 此外，它将提供针对继发性血管神经炎的效用的概念证明。 损害作为防止或延缓未来认知衰退的一种手段。理想情况下，这种方法总有一天会 纳入管理AD风险的综合战略。精心设计的职业发展 计划也已正式确定，其中包括参加专门讲习班、定期提交数据、 参加科学会议和提高非技术性科学能力。一位经验丰富的人 由资深科学家组成的指导组，在一个成熟的AD研究机构，确保我将拥有 成长为致力于AD治疗开发的成功的独立调查者的最佳机会。