Relating Neuroimmune and Neurovascular Alterations During Alzheimer's Disease Progression

摘要 这个项目将探讨如何改变神经免疫相互作用，神经血管信号，和大脑 代谢导致阿尔茨海默病（AD）病理学，沿着运动的潜在益处（又名 体力活动）。考虑到临床预后后认知和功能的迅速，积极恶化 以及AD对日益老龄化的人口构成的可怕威胁，目前缺乏治疗技术， AD发病和进展的早期、强有力的诊断标志物构成了现代诊断的关键挑战。 健康护理除了强烈相关的病理标志，如淀粉样蛋白-β的积累， 低聚物/斑块和神经细胞缠结，AD进展涉及明显的神经炎性 中枢神经系统细胞如小胶质细胞和星形胶质细胞的反应，以及脑血流、能量 代谢和细胞信号传导。据报道，这些过程在首次出现症状前几年就开始了。 认知能力的下降变得明显。因为没有一个单独的临床前AD症状与 认知障碍，解开这些病理改变之间的关系和相互依赖性 为了更好地理解AD复杂的发病机制，需要对复杂的 细胞和血管的相互作用，在临床前模型的活体大脑中具有高空间分辨率。此外，委员会认为， 尽管保护机制尚不清楚，但体力活动显示出减少这种可能性的希望。 和老年受试者中认知损害的严重程度。使用各种定制设计的高级 显微镜方法，我们将探讨，在细胞和微血管水平，如何看似不同的， 神经免疫和脑血管的变化是相互关联的，以及它们如何共同促进 AD临床前小鼠模型中的毁灭性AD相关神经变性。我们还将研究如何 体力活动可以减轻这些神经免疫和神经血管的改变。结果会帮助我们 更详细地了解大脑中随之而来的多方面结构和功能变化， 在临床上可观察到的认知缺陷出现之前的20年，它们将有助于指导新的早期认知缺陷。 干预和治疗策略，以尽量减少AD相关的认知退化。

ABSTRACT This project will explore how alterations in neuroimmune interactions, neurovascular signaling, and cerebral metabolism contribute to Alzheimer's disease (AD) pathology, along with the potential benefits of exercise (aka physical activity). Given the rapid, aggressive deterioration in cognition and function following clinical prognosis and the dire threat that AD poses to the rising aging population, the current lack of therapeutic techniques and early, robust diagnostic markers of AD onset and progression constitutes a critical challenge for modern healthcare. In addition to strongly associated pathological hallmarks such as accumulation of amyloid-β oligomers/plaques and neurofibrillary tangles, AD progression involves a pronounced neuroinflammatory response from CNS cells like microglia and astrocytes, as well as impairments to cerebral blood flow, energy metabolism, and cellular signaling. These processes reportedly initiate several years before the first symptoms of cognitive decline become evident. Because no individual preclinical AD symptom correlates perfectly with cognitive impairment, untangling the relationships and interdependencies between these pathological alterations is necessary to better understand the complex pathogenesis of AD, and it requires characterization of intricate cellular and vascular interactions with high spatial resolution in living brains of preclinical models. Furthermore, although the protective mechanisms remain unclear, physical activity shows promise for reducing the likelihood and severity of cognitive impairment in elderly subjects. Using a broad assortment of custom-designed advanced microscopy methods, we will explore, at the cellular and microvascular level, how seemingly distinct neuroimmune and cerebrovascular changes are interrelated and how they collectively contribute to the devastating AD-related neurodegeneration in preclinical mouse models of AD. We will also investigate how physical activity can mitigate these neuroimmune and neurovascular alterations. The results will help us understand in much greater detail the multifaceted structural and functional changes that ensue in the brain over the ~2 decades before clinically-observable cognitive deficiencies manifest, and they will help guide new early intervention and treatment strategies to minimize AD-related cognitive degradation.