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

阿尔茨海默氏病 [AD] 是一种进行性退行性疾病，其病因尚不清楚，且可缓解疾病 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对神经元活动的调节，从小血管传导到 更大的血管和对神经元活动的血流动力学反应。神经血管调节机制 在大脑老化的背景下，可以将其与过早衰老和进行性衰老区分开来 与 AD 和痴呆综合征相关的神经退行性变。早期病理性神经血管和 代谢改变可以减少向 AD 大脑的底物输送。尽管大脑的新陈代谢在 随着年龄的增长，AD 表现出比同龄人更严重和过早的代谢功能不全 控制，归因于多个水平的神经血管失调。 我们将分析年龄匹配的对照基因型（两者）中发生的神经血管调节机制 野生型 C57Bl/6 和 mNOS2-/-) 与 CVN-AD 动物中注意到的进行性退化相比 阿尔茨海默病模型（APPSwDI / mNos2−/−）。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 蛋白和严重的 神经变性。我们的假设是退化，正如人类 AD 和相关 CVN-AD 中所指出的那样 动物模型中，由于毛细血管、周细胞、 传导和血流动力学水平。代谢不足尤其可能由异常引起 神经血管耦合和从小血管到大血管的传导，削弱了血流动力学反应 动态神经元活动。 CVN-AD 模型反映了人类 AD 表型，可预测的时间过程为 与衰老变化相关的行为、血管和回路退化因此提供了适当的预治疗 用于分析这些概念的临床转化模型。我们将研究新的评估方法 神经血管调节机制，包括周细胞、壁细胞的化学遗传学方法 水平，评估对较大容量脑血管的活动和传导、神经血管耦合和 血流动力学反应，了解底物关键时刻灌注不足的动态机制 海马体和新皮质的需求是基因型、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.