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

AD 脑病理学中的低灌注、血流动力学控制域和神经血管失调

基本信息

批准号：
10654258
负责人：
DENNIS Alan TURNER
金额：
$ 50.14万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654258
关键词：
Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Animal Disease Models Animals Behavioral Blood Vessels Blood capillaries Blood flow Brain Brain Pathology Cell Wall Cerebrovascular Circulation Cerebrum Clinical Cyclophilin A Degenerative Disorder Dementia Disease Disease Progression Elements Etiology Future G-Protein-Coupled Receptors Gender Genes Genetic Genotype Glucose Glutamates Goals Hippocampus Human Hyperemia Hypoxia In Vitro Intervention Link Longevity Memory Metabolic Metabolism Modeling Mus Neocortex Nerve Degeneration Neurons Pathologic Pathway interactions Pericytes Phenotype Phosphatidylinositol 4,5-Diphosphate Physiological Physiology Population Potassium Channel Premature aging syndrome Regulation Risk Factors Senile Plaques Signal Transduction Slice Stereotyping Stroke Synapses Syndrome Time Tissues Training Vasodilation age effect age related aging brain analog apolipoprotein E-4 brain metabolism cerebrovascular cholinergic constriction designer receptors exclusively activated by designer drugs disease phenotype experience extracellular genetic approach hemodynamics hypoperfusion improved in vivo metabolic rate metabolomics mouse model neocortical neural neurotransmission neurovascular neurovascular coupling novel strategies patch clamp pre-clinical premature prevent progressive neurodegeneration response spreading depression tau-1 translational model treatment strategy

项目摘要

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.

阿尔茨海默氏病[AD]是一种不清晰病因和疾病修改的程序性退化性的疾病治疗仍然难以捉摸。具有神经元活性的毛细管和小血管周围调节，从小血管到较大的血管和对神经元活性的血液动力学反应在衰老的背景下，大脑可以与过早的衰老和进步区分开与AD和痴呆综合征相关的神经变性。新陈代谢的改变可以减少向广告大脑的底物递送。与年龄匹配相比对照，归因于多个级别的神经血管失调。我们将分析年龄匹配的对照基因型中发生的神经血管调节的机制（Bothh 与CVN-AD动物中指出的进行性变性相比，WildType C57BL/6和MNOS2 - / - ）阿尔茨海默氏病的模型（appswdi + / + mnos2 - / - ）。表型变化，尤其是血管周围的淀粉样蛋白斑块，磷酸化的tau和严重神经变性是我们的假设动物模型会因毛细管毛细管供应的过早老化变化而恶化传导和血液动力学水平。神经血管耦合和从小血管到较大血管的连接，使血液动力学呼吸趋于动态神经活性。与衰老变化有关的行为，血管和电路变性变性。分析这些概念的临床，翻译模型。神经血管调节的机制，包括周细胞，壁壁细胞的化学发生方法水平，评估较大容量大脑血管的活动和受孕，神经血管耦合和血流动力学反应，以了解底物关键时期下灌注的动态机制在海马和新皮层中的需求是基因型，性别和年龄的函数。