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: 10343669
• 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/10343669
• 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; SARS-CoV-2 P.1; Secondary to; Sodium Chloride; Structure; Superoxides; Testing; Transgenic Organisms; 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; hypertensive; 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，尤其是 尽管老年高血压成年人表现出肌原反应受损（MR）和自动调节 脑血流（CBF），所涉及的基因和机制及其对高血压相关的贡献 痴呆症没有完全阐明。该建议是我的R21申请（AG050049）的直接扩展 由Nia ASG开发了动物模型来研究ADD3在介导认知中的作用 衰老的障碍。我们涉及社区动脉粥样硬化风险的遗传分析神经认知 研究表明，γ-无元（ADD3）的变体与痴呆有关。在动物研究中，我们 在FHH大鼠的ADD3基因中遗传映射了损害脑MR和自动调节的突变。期间 资助的R21时期，我们生成并表征了ADD3转基因大鼠，并确认改进了 ADD3表达是脑血液动力学受损的驱动力，因此导致血脑 屏障（BBB）泄漏，感染以及最终的海马神经元和认知功能的丧失 衰老和高血压。我们的新初步数据表明，add3损坏肌动蛋白的下调 细胞骨架结构，降低肌动蛋白稳定并提高原发性脑中的超氧化物的产生 从FHH大鼠分离的VSMC。在用add3处理的神经胶质细胞中也观察到相同的结构变化 dsirna。另外，FHH大鼠大脑中的Aβ蛋白表达早在8周龄时就开始增加。 高血压FHH大鼠的毛细血管周围有线粒体损伤。线粒体 在用ADD3 DSIRNA处理的神经胶质细胞中，呼吸和ATP产生受到损害。基于这个证据， 我们假设减少了ADD3表达uncoles F-肌动蛋白锚定在膜上并增强 异常肌动蛋白聚合，会损害CBF自动调节并促进认知的发展 通过减弱脑血管细胞收缩，降低神经胶质Aβ的清除率，衰老 - 亚升压的损害 并加剧脑血管线粒体功能障碍。我们将在正常SD上使用ADD3基因KO大鼠 遗传背景和药物干预措施以确定增强的肌动蛋白聚合是否改变了MR 可以解释CBF自动调节，BBB泄漏，神经变性和 失智。我们还将确定Aβ清除率和脑血管线粒体是否降低 ADD3 KO大鼠功能障碍。拟议的研究的结果将确定衰老的亚型 促进CBF自动调节受损，导致认知缺陷。未发现的机制将 解决关键的知识差距，以更好地了解ADD3的下调是否是危险因素 与年龄和高血压相关痴呆的发展。这将为发现小说奠定基础 恢复CBF自动调节的生物标志物和药物，以防止发作并减缓痴呆症的进展 在老年人中。