Relating Neuroimmune and Neurovascular Alterations During Alzheimer's Disease Progression

摘要 这个项目将探索神经免疫相互作用、神经血管信号和大脑 代谢有助于阿尔茨海默病(AD)的病理，以及运动的潜在好处(又名 体力活动)。考虑到临床预后后认知和功能的迅速、侵略性的恶化 AD对日益增长的老龄化人口构成的可怕威胁，目前缺乏治疗技术和 AD发病和进展的早期、强有力的诊断标记物对现代 医疗保健。除了强烈相关的病理特征，如淀粉样蛋白-β堆积 寡聚体/斑块和神经原纤维缠结，AD进展涉及明显的神经炎性 小胶质细胞和星形胶质细胞等中枢神经系统细胞的反应以及对脑血流、能量的损害 新陈代谢和细胞信号。据报道，这些过程在最初症状出现前几年就开始了。 认知能力下降的可能性变得明显。因为没有一个个体的临床前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 为了更好地了解AD的复杂发病机制，需要对错综复杂的 临床前模型活体大脑中具有高空间分辨率的细胞和血管相互作用。此外， 尽管保护机制尚不清楚，但体力活动显示出降低这种可能性的希望。 老年受试者认知功能障碍的严重程度。使用各种定制设计的高级 显微镜方法，我们将探索，在细胞和微血管水平，如何看似不同 神经免疫和脑血管变化是相互关联的，它们是如何共同作用于 临床前阿尔茨海默病小鼠模型中与阿尔茨海默病相关的破坏性神经变性。我们还将调查如何 体育活动可以减轻这些神经免疫和神经血管的改变。结果将对我们有所帮助 更详细地了解随之而来的大脑结构和功能的多方面变化 在临床可观察到的认知缺陷显现之前约20年，它们将有助于指导新的早期 干预和治疗策略，以最大限度地减少与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.