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

阿尔茨海默病（Alzheimer's Disease，AD）是一种病因不明的进行性退行性疾病， 治疗仍然难以捉摸。异常的神经血管调节可导致对脑的底物供应减少， 包括毛细血管和小血管周细胞的调节与神经元的活动，从小血管传导到 更大规模的血管，以及对神经元活动的血液动力学反应。神经血管调节机制 在大脑老化的背景下，可以从过早衰老和渐进性衰老中区分出来。 与AD和痴呆综合征相关的神经变性。早期病理性神经血管和 代谢改变可减少底物递送至AD脑。虽然大脑的新陈代谢在 与年龄匹配的相比，AD表现出更严重和过早的代谢功能不全 对照组，归因于多个水平的神经血管失调。 我们将分析发生在年龄匹配的对照基因型中的神经血管调节机制（两者都是）。 野生型C57 B1/6和mNOS 2-/-）与在CVN-AD动物中观察到的进行性变性相比 阿尔茨海默病模型（APPSwDI +/+ mNos 2 −/−）。这种独特的小鼠模型非常接近人类 表型变化，特别是血管周围的淀粉样斑块，磷酸化tau蛋白，以及严重的 神经变性我们的假设是，如在人类AD和相关的CVN-AD中所注意到的， 动物模型，由于毛细血管，周细胞， 传导和血液动力学水平。代谢功能不全特别是由异常 从小血管到大血管的神经血管耦合和传导，使血流动力学反应减弱， 动态神经元活动CVN-AD模型反映了人类AD表型，具有可预测的时间进程， 行为、血管和回路退化与年龄变化的关系，因此提供了一个适当的预 临床的、转化的模型来分析这些概念。我们将研究新的方法来评估 神经血管调节的机制，包括周细胞、壁细胞的化学发生途径 水平，评估活动和传导到更大容量的脑血管，神经血管耦合和 血流动力学反应，以了解在基质的关键时刻低灌注的动力学机制 需要，在海马和新皮层作为基因型，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.