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.

摘要 血管性认知障碍和痴呆（VCID）是痴呆的第二大原因， 阿尔茨海默病（AD）。此外，VCID是AD的常见并发症，使诊断复杂化， 治疗AD患者的显著比例。尽管VCID普遍存在，但相对而言， 与AD相比，研究不足，并且对认知障碍的分子机制知之甚少。 脑血管疾病导致的机能障碍。在某种程度上，这是由于多种病理过程 破坏神经血管网络导致血管性痴呆 我们以前已经证明，星形胶质细胞终足在存在以下情况时受到显著影响： 脑淀粉样血管病（CAA），星形胶质细胞终足与血管系统的接触减少。此外，本发明还 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， 星形胶质细胞末端足的Kir4.1和BK通道。我们通过归纳建立了一个VCID模型， 高同型半胱氨酸血症（HHcy）我们已经证明，野生型小鼠的这种模型与多种 微血管扩张、血流量减少、神经炎症和认知障碍。我们现在有了有趣的 初步数据表明，我们在CAA中观察到的星形胶质细胞中存在相同的病理变化， 也发生在我们的VCID的HHcy模型中。 在本研究中，我们将使用VCID的HHcy模型。我们将检验这个假设， 星形胶质细胞末端破坏导致神经元功能障碍， HHcy模型对于星形胶质细胞终足的破坏是至关重要的。我们制定了三个具体目标。 目标1。验证星形胶质细胞终足破坏导致神经元功能障碍和受损的假设。 钾稳态 目标2.验证MMP 9是星形胶质细胞终足脱离的重要介质这一假设。 VCID的血管。 目标3.检验星形胶质细胞终足破坏是脑胶质细胞瘤的常见病理特征这一假设。 VCID的脑血管病变。