Adducin, actin cytoskeleton and cognitive impairments

内收蛋白、肌动蛋白细胞骨架和认知障碍

• 批准号: 9897521
• 负责人: Fan Fan
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9897521
• 关键词: Abeta clearance; Actin-Binding Protein; Actins; Address; Adult; Age; Aging; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Animals; Astrocytes; Atherosclerosis Risk in Communities; Attenuated; Blood - brain barrier anatomy; Blood capillaries; Brain; Cell Maintenance; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Cognition; Cognitive deficits; Communities; Cytoskeleton; DOCA; Data; Dementia; Development; Disease; Down-Regulation; Elderly; Endocytosis; Extravasation; F-Actin; Foundations; Funding; G Actin; Genes; Genetic; Hippocampus (Brain); Homeostasis; Hypertension; Impaired cognition; Impairment; Individual; Inflammation; Intervention; Knock-out; Knowledge; Maps; Mediating; Membrane; Memory Loss; Memory impairment; Microglia; Mitochondria; Modeling; Molecular; Morphology; Motor; Mutation; Nerve Degeneration; Neurocognitive; Neurodegenerative Disorders; Neuroglia; Neurons; Organelles; Pathologic; Pharmacologic Substance; Pharmacology; Play; Predisposition; Production; Rattus; Respiration; Risk Factors; Role; Secondary to; Sodium Chloride; Structure; Superoxides; Testing; Transgenic Organisms; Variant; Vascular Dementia; adducin; arm; arteriole; base; cell motility; cerebral artery; cerebral hemodynamics; cerebrovascular; cognitive development; cognitive function; constriction; dementia risk; driving force; gamma-adducin; genetic analysis; high risk; knockout gene; middle cerebral artery; mitochondrial dysfunction; normotensive; novel; novel marker; novel therapeutic intervention; novel therapeutics; polymerization; prevent; protein expression; response; spatial memory; trafficking; uptake; water maze

PROJECT SUMMARY/ABSTRACT Hypertension is one of the leading risk factors for cerebrovascular disease and cognitive impairments, especially with aging. Although older hypertensive adults display impaired myogenic response (MR) and autoregulation of cerebral blood flow (CBF), the genes and mechanisms involved and their contribution to hypertension-related dementia are not fully elucidated. This proposal is a direct extension of my R21 application (AG050049) funded by NIA ASG in which we developed animal models to investigate the role of Add3 in mediating cognitive impairments with aging. Our genetic analysis involving the Atherosclerosis Risk in Communities Neurocognitive Study revealed that variants of gamma-adducin (ADD3) are associated with dementia. In animal studies, we genetically mapped a mutation in the Add3 gene in FHH rats that impairs cerebral MR and autoregulation. During the funded R21 period, we generated and characterized Add3 transgenic rats and confirmed that decreased Add3 expression is a driving force for impaired cerebral hemodynamics, which consequently leads to blood-brain barrier (BBB) leakage, inflammation, and ultimately loss of hippocampal neurons and cognitive function upon aging and hypertension. Our new preliminary data demonstrate that downregulation of Add3 damages actin cytoskeletal structure, reduces actin stabilization, and elevates superoxide production in primary cerebral VSMCs isolated from FHH rats. The same structural changes are also observed in glial cells treated with Add3 DsiRNA. In addition, Aβ protein expression in the brain of FHH rats starts to increase as early as 8 weeks of age. There is mitochondrial damage in the brain surrounding leaky capillaries in hypertensive FHH rats. Mitochondrial respiration and ATP production are compromised in glial cells treated with Add3 DsiRNA. Based on this evidence, we HYPOTHESIZE that reduced Add3 expression uncouples F-actin anchoring to the membrane and enhances aberrant actin polymerization, which impairs CBF autoregulation and promotes development of cognitive impairments in aging-hypertension by attenuating cerebrovascular cell constriction, reducing glial Aβ clearance, and exacerbating cerebral vascular mitochondrial dysfunction. We will use Add3 gene KO rat on normal SD genetic background and pharmaceutical interventions to determine if enhanced actin polymerization alters MR of cerebral arteries, which could explain impaired CBF autoregulation, BBB leakage, neurodegeneration, and dementia. We will also determine if there is diminished Aβ clearance and cerebral vascular mitochondrial dysfunction in Add3 KO rats. The results from the proposed studies will establish that aging-hypertension promotes impaired CBF autoregulation, contributing to cognitive deficits. The uncovered mechanisms will address a critical knowledge gap to better understand whether downregulation of ADD3 is a risk factor for development of age- and hypertension-related dementia. This will lay the foundation for discovery of novel biomarkers and drugs that restore CBF autoregulation to prevent the onset and slow the progression of dementia in elderly hypertensive individuals.

项目摘要/摘要 高血压是脑血管疾病和认知障碍的主要危险因素之一， 随着年龄的增长。尽管老年高血压患者显示出肌源性反应（MR）受损， 脑血流量（CBF）、相关基因和机制及其在高血压相关性脑血管病中的作用 痴呆症尚未完全阐明。此提案是我的R21申请（AG 050049）资助的直接扩展 NIA ASG开发了动物模型来研究Add 3在介导认知功能中的作用， 衰老带来的损伤我们的遗传分析涉及社区神经认知的动脉粥样硬化风险 研究表明，γ-内收蛋白（ADD 3）的变体与痴呆症有关。在动物实验中，我们 在FHH大鼠的Add 3基因中，对一个损害大脑MR和自动调节的突变进行了基因定位。期间 在R21期间，我们产生并表征了Add 3转基因大鼠，并证实了 Add 3表达是脑血流动力学受损的驱动力，其因此导致血脑 结果表明，在脑缺血后，脑屏障（BBB）渗漏、炎症和最终海马神经元和认知功能的丧失， 衰老和高血压。我们的新的初步数据表明，下调Add 3损伤肌动蛋白 细胞骨架结构，减少肌动蛋白稳定，并提高超氧化物的产生，在原发性脑 从FHH大鼠分离的VSMC。在用Add 3处理的神经胶质细胞中也观察到相同的结构变化 DsiRNA。此外，FHH大鼠脑中的Aβ蛋白表达早在8周龄时就开始增加。 高血压FHH大鼠脑毛细血管渗漏周围存在线粒体损伤。线粒体 在用Add 3DsiRNA处理的神经胶质细胞中，呼吸和ATP产生受到损害。基于这些证据， 我们假设Add 3表达的减少使F-肌动蛋白与细胞膜的锚定解除偶联， 肌动蛋白聚合异常，损害CBF自动调节并促进认知发育 通过减弱脑血管细胞收缩，减少胶质Aβ清除， 并加重脑血管线粒体功能障碍。我们将使用Add 3基因KO大鼠对正常SD大鼠 遗传背景和药物干预，以确定是否增强肌动蛋白聚合改变MR 这可以解释受损的CBF自动调节，BBB泄漏，神经变性， 痴呆我们还将确定Aβ清除率是否降低， Add 3 KO大鼠的功能障碍。从拟议的研究结果将建立，老龄化高血压 促进受损的CBF自动调节，导致认知缺陷。未被发现的机制将 解决关键的知识差距，以更好地了解ADD 3的下调是否是一个风险因素， 与年龄和高血压相关的痴呆症的发展。这将为小说的发现奠定基础 恢复CBF自动调节以预防痴呆发作和减缓痴呆进展的生物标志物和药物 老年高血压患者。