Hypoperfusion, Hemodynamic Control Domains and Neurovascular Dysregulation in AD brain pathology

阿尔茨海默病[AD]是一种病因不明、发病机制不清的进行性退行性疾病 治疗方法仍然难以捉摸。神经血管调节异常会导致大脑底物供应减少， 包括毛细血管和小血管周细胞与神经元活动的调节，从小血管到 更大的血管，以及对神经元活动的血液动力学反应。神经血管调节机制 在老龄化的背景下，大脑可以区分为过早衰老和进行性衰老 与阿尔茨海默病和痴呆综合征相关的神经变性。早期病理性神经血管和 代谢改变会减少底物向AD大脑的输送。虽然大脑的新陈代谢在 与年龄匹配的人相比，老年性痴呆表现出更严重和更早的代谢不足 对照组，可归因于多个层面的神经血管失调。 我们将分析年龄匹配的对照基因(两者)中发生的神经血管调节机制 野生型C57BL/6和mNOS2-/-)与CVN-AD动物中记录的进行性退行性变进行比较 阿尔茨海默病模型(APPSwDI/mNos2−/−)。这一独特的老鼠模型与人类非常相似 表型改变，特别是血管周围的淀粉样斑块，磷酸化的tau，严重的 神经退行性变。我们的假设是变性，正如在人类AD和相关的CVN-AD中所注意到的那样 动物模型，由于毛细血管，周细胞， 传导和血流动力学水平。新陈代谢不足，特别是异常时会引起。 神经血管偶联和从小血管到大血管的传导，钝化血流动力学反应 动态神经元活动。CVN-AD模型反映了人类AD的表型，具有可预测的时间进程 因此，与衰老变化相关的行为、血管和回路退化提供了适当的预 用于分析这些概念的临床、翻译模型。我们将研究新的评估方法 神经血管调节机制包括周细胞、壁细胞的化学发生途径 水平，评估活动和对较大容量脑血管的传导，神经血管耦合和 血流动力学反应，以了解底物危重时刻低灌流的动力学机制 需要，在海马体和新皮质作为一个基因，性别和年龄的函数。

Alzheimer’s Disease [AD] is a progressive degenerative disorder of unclear etiology and disease-modifying treatments remain elusive. Abnormal neurovascular regulation can lead to reduced substrate supply to brain, including capillary and small vessel pericyte regulation with neuronal activity, conduction from small vessels to larger scale vessels, and hemodynamic responses to neuronal activity. Neurovascular regulation mechanisms in the context of the aging brain can be differentiated from the premature aging and progressive neurodegeneration associated with AD and dementia syndrome. Early pathological neurovascular and metabolic alterations can reduce substrate delivery to the AD brain. Though brain metabolism is altered during aging, AD demonstrates more severe and premature metabolic insufficiency in comparison to age-matched controls, attributable to neurovascular dysregulation at multiple levels. We will analyze mechanisms of neurovascular regulation occurring in age-matched control genotypes (both wildtype C57Bl/6 and mNOS2-/-) compared to the progressive degeneration noted in the CVN-AD animal model of Alzheimer’s disease (APPSwDI +/+ mNos2−/−). This unique mouse model closely mirrors human phenotypic changes, particularly amyloid plaques around blood vessels, phosphorylated tau, and severe neurodegeneration. Our hypothesis is that degeneration, as noted in both human AD and the relevant CVN-AD animal model, is worsened by premature aging changes in substrate supply at the capillary, pericyte, conduction, and hemodynamic levels. Metabolic insufficiency can arise particularly from abnormal neurovascular coupling and conduction from small to larger vessels, blunting the hemodynamic response to dynamic neuronal activity. The CVN-AD model mirrors human AD phenotypes with a predictable time course of behavioral, vascular and circuit degeneration in relation to aging changes hence provides an appropriate pre- clinical, translational model for analyzing these concepts. We will study novel approaches to evaluating mechanisms of neurovascular regulation including chemogenetic approaches at the pericyte, mural wall cell level, assessing activity and conduction to larger capacity cerebral vessels, neurovascular coupling and hemodynamic responses, to understand dynamic mechanisms of hypoperfusion at critical times of substrate need, in both hippocampus and neocortex as a function of genotype, gender, and age.