Neurovascular astrocyte dysfunction in VCID

VCID 中的神经血管星形胶质细胞功能障碍

• 批准号: 9306465
• 负责人: Donna M Wilcock
• 金额: $ 37.59万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306465
• 关键词: Alzheimer' s Disease; Astrocytes; Autopsy; Basal lamina; Biochemical; Blood flow; Brain; Cerebral Amyloid Angiopathy; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Characteristics; Comorbidity; Data; Dementia; Diagnosis; Dystroglycan; Electrophysiology (science); Environment; Enzymes; Extracellular Matrix; Family; Functional disorder; Gene Expression; Glial Fibrillary Acidic Protein; Histologic; Homeostasis; Human; Hyperhomocysteinemia; Impaired cognition; Impairment; Inhibition of Matrix Metalloproteinases Pathway; Interleukin-1 beta; Knockout Mice; MMP9 gene; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Mediator of activation protein; Methods; Modeling; Molecular; Morphology; Mus; Neuroglia; Neuronal Dysfunction; Neurons; Pathologic; Pathologic Processes; Pathology; Patients; Pharmacology; Pilot Projects; Potassium; Prevalence; Proteins; Research Proposals; Role; TNF gene; Testing; Time; Tissues; aquaporin 4; behavioral outcome; cerebrovascular; foot; human tissue; large-conductance calcium-activated potassium channels; mouse model; neuroinflammation; neurovascular; protein expression; vascular cognitive impairment and dementia

Abstract Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia behind Alzheimer's disease (AD). In addition, VCID is a frequent co-morbidity with AD, complicating the diagnosis and treatment of AD for a significant proportion of AD patients. Despite its prevalence, VCID remains relatively understudied compared to AD, and little is known about the molecular mechanisms underlying the cognitive dysfunction resulting from cerebrovascular disease. In part, this is due to the multiple pathological processes disrupting neurovascular networks that can result in VaD. We have previously shown that astrocytic end-feet are significantly impacted in the presence of cerebral amyloid angiopathy (CAA), with decreased contact of astrocytic end-feet with the vasculature. Further, these morphological changes in the astrocyte were associated with decreased expression of aquaporin 4, Kir4.1 and BK channels at the astrocytic end-feet. We have developed a model of VCID through the induction of hyperhomocysteinemia (HHcy). We have shown that this model in wildtype mice is associated with multiple microhemorrhages, reduced blood flow, neuroinflammation and cognitive impairment. We now have intriguing preliminary data that indicates these same pathological changes in the astrocytes that we observed with CAA also occur in our HHcy model of VCID. In this research proposal we will use the HHcy model of VCID. We will test the hypothesis that astrocyte end-foot disruption contributes to neuronal dysfunction and that the activation of MMP9 in the HHcy model is critical to the disruption of the astrocytic end-feet. We have developed 3 specific aims. Aim 1. Test the hypothesis that astrocytic end-foot disruption leads to neuronal dysfunction and impaired potassium homeostasis. Aim 2. Test the hypothesis that MMP9 is an essential mediator of astrocyte end-foot detachment from the cerebrovasculature with VCID. Aim 3. Test the hypothesis that astrocytic end-foot disruption is a common pathological characteristic of cerebrovascular pathologies of VCID.

抽象的 血管认知障碍和痴呆症（VCID）是痴呆症的第二主要原因 阿尔茨海默氏病（AD）。此外，VCID是与AD的常见合并症，使诊断和复杂 AD治疗很大一部分的AD患者。尽管率高，但VCID仍然相对 与AD相比，研究对认知的分子机制几乎没有知识 脑血管疾病引起的功能障碍。部分原因是由于多个病理过程 破坏可能导致VAD的神经血管网络。 我们先前已经表明，在存在的情况下，星形细胞端远受到了显着影响 脑淀粉样血管病（CAA），星形胶质细胞末端与脉管系统的接触降低。更远， 星形胶质细胞中的这些形态学变化与水通道蛋白4的表达降低有关 kir4.1和BK通道在星形胶质细胞末端。我们已经通过诱导开发了VCID模型 高层结晶血症（HHCY）。我们已经表明，野生型小鼠中的该模型与多个相关 微诊断，血液流量减少，神经炎症和认知障碍。我们现在很有趣 初步数据，表明我们使用CAA观察到的星形胶质细胞中的这些相同的病理变化 也发生在我们的VCID HHCY模型中。 在这项研究建议中，我们将使用VCID的HHCY模型。我们将检验以下假设 星形胶质细胞末端破坏会导致神经元功能障碍，并激活MMP9 HHCY模型对于破坏星形胶质细胞末端至关重要。我们已经开发了3个具体目标。 目的1。检验星形细胞末端破坏导致神经元功能障碍并受损的假设 钾稳态。 AIM 2。检验MMP9是星形胶质细胞末端脱离的基本介体的假设 带有VCID的大脑。 目的3。检验星形胶质细胞末尾破坏是常见的病理特征的假设 VCID的脑血管病理。