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 血管认知障碍和痴呆(VCID)是仅次于痴呆症的第二大原因 阿尔茨海默病(AD)。此外，VCID是一种常见的AD并存疾病，使诊断和 治疗AD的患者中有相当一部分是AD患者。尽管VCID很普遍，但VCID仍然相对 与AD相比，研究不足，对认知障碍背后的分子机制知之甚少 脑血管疾病引起的功能障碍。这在一定程度上是由于多种病理过程所致。 扰乱神经血管网络，可能导致血管性痴呆。 我们以前已经证明，星形细胞末端足在存在的情况下受到显著影响。 脑淀粉样血管病(CAA)，星形细胞末端足部与血管系统接触减少。此外， 星形胶质细胞的这些形态变化与水通道蛋白4的表达减少有关， KIR4.1和BK通道位于星形细胞末端足部。我们通过归纳建立了一种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个 微出血、血流量减少、神经炎症和认知障碍。我们现在有了耐人寻味的 初步数据表明，这些星形胶质细胞的病理变化与我们用CAA观察到的相同 在我们的VCID HHcy模型中也会发生。 在本研究方案中，我们将使用VCID的HHcy模型。我们将检验这一假设 星形胶质细胞末端足部断裂导致神经元功能障碍，MMP9在脑内的激活 HHcy模型对星形细胞终足的破坏至关重要。我们制定了三个具体目标。 目的1.检验星形细胞末端足部损伤会导致神经元功能障碍和损伤的假说 钾动态平衡。 目的2.验证MMP9是星形胶质细胞足底脱离的重要介质的假说。 脑血管病合并VCID。 目的3.检验星形细胞样末端足部断裂是脑膜瘤常见病理特征的假说 VCID的脑血管病理改变。