Neuroinflammatory mechanisms of aging-related vascular cognitive impairment (VCI)

衰老相关血管性认知障碍（VCI）的神经炎症机制

基本信息

批准号：
9461247
负责人：
Nabil J Alkayed
金额：
$ 249.53万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9461247
关键词：
Acids Affect Age Age-associated memory impairment Aging Alzheimer&apos s Disease Animal Model Anti-Inflammatory Agents Anti-inflammatory Autopsy Binding Blood - brain barrier anatomy Blood Vessels Blood capillaries Brain CD45 Antigens Cells Cerebral small vessel disease Cerebrovascular Circulation Chronic Data Dementia Diabetes Mellitus Disease Eicosanoids Endothelium Enzymes Epoxide hydrolase Feedback Fluorescence-Activated Cell Sorting Frequencies High Fat Diet Human Hydrolase ITGAM gene Impaired cognition Impairment Infiltration Inflammation Inflammatory Invaded Leukocytes Ligands Link LoxP-flanked allele Mediating Memory Loss Memory impairment Microglia Microvascular Dysfunction Migration Inhibitory Factor Mus Neuronal Injury Neurotoxins Non-Insulin-Dependent Diabetes Mellitus PTPRC gene Patients Permeability Pharmaceutical Preparations Pharmacology Phenotype Plasma Play Production Recombinants Risk Factors Role T-Cell Receptor Testing Therapeutic Transgenic Mice Transgenic Organisms Up-Regulation Vascular Cognitive Impairment Vascular Dementia Vascular Diseases Vasodilator Agents Wild Type Mouse age related arteriole artery occlusion brain tissue capillary cerebral hypoperfusion cerebrovascular cytokine density enzyme activity hypoperfusion macrophage macrophage migration inhibitory factor receptor mild cognitive impairment mind control monocyte morris water maze mouse model neuroinflammation neuron loss neurovascular injury overexpression prevent promoter sex spatial memory

项目摘要

Project Summary Vascular cognitive impairment (VCI) is the second most common cause of dementia after Alzheimer's disease (AD). The mechanisms underlying VCI are poorly understood, with no specific therapy currently exists to prevent or treat VCI. We have previously observed increased expression and activity of the enzyme soluble epoxide hydrolase (sEH) in microvascular endothelium of human brain tissue from deceased patients with pre-mortem VCI. We have also observed in mice that high-fat diet (HFD)-induced type 2 diabetes causes a similar increase in cerebrovascular sEH. Our preliminary data demonstrate that transgenic mice with constitutive overexpression of human sEH in endothelium (Tie2-hsEH) have impaired spatial memory (Morris Water Maze), suggesting that endothelial sEH is causally linked to cognitive impairment. Proposed studies will determine if endothelial sEH upregulation impairs cognition by a neuro-inflammatory mechanism mediated by infiltration of brain tissue by monocyte-derived macrophages. Studies will also determine if mice with endothelial-specific deletion of sEH (Tie2-Cre/floxed-sEH) are protected from HFD-induced neuronal loss, neuroinflammation and cognitive impairment. Finally, we will use two different therapies, one aimed at inhibiting sEH and one aimed at preventing monocyte/macrophage infiltration, to determine if these agents can prevent (when given prior to cognitive decline) or reverse (when given after cognitive impairment) the age-related cognitive deficit in Tie2-hsEH mice and wild-type mice on HFD.

项目概要血管性认知障碍（VCI）是继阿尔茨海默氏病之后导致痴呆的第二常见原因（广告）。人们对 VCI 的机制知之甚少，目前还没有具体的治疗方法来预防或治疗 VCI。我们之前观察到酶溶性环氧化物的表达和活性增加死者生前人脑组织微血管内皮中的水解酶（sEH）气相防锈。我们还在小鼠身上观察到，高脂饮食 (HFD) 诱发的 2 型糖尿病会导致类似的增加在脑血管 sEH 中。我们的初步数据表明，具有组成型过度表达的转基因小鼠内皮细胞中的人类 sEH (Tie2-hsEH) 会损害空间记忆 (Morris 水迷宫)，这表明内皮 sEH 与认知障碍有因果关系。拟议的研究将确定内皮 sEH 是否上调通过脑组织浸润介导的神经炎症机制损害认知单核细胞来源的巨噬细胞。研究还将确定具有内皮特异性 sEH 缺失的小鼠是否 (Tie2-Cre/floxed-sEH) 免受 HFD 引起的神经元损失、神经炎症和认知障碍的影响损害。最后，我们将使用两种不同的疗法，一种旨在抑制 sEH，另一种旨在预防单核细胞/巨噬细胞浸润，以确定这些药物是否可以预防（当在认知之前给予时） Tie2-hsEH 小鼠中年龄相关的认知缺陷下降）或逆转（在认知障碍后给予）和服用 HFD 的野生型小鼠。