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.

项目摘要血管认知障碍（VCI）是仅次于阿尔茨海默氏病的第二常见痴呆症原因（广告）。 VCI的基础机制知之甚少，目前尚无特定疗法以防止或治疗VCI。我们先前已经观察到酶可溶性环氧的表达和活性增加死者验尸患者的人脑组织微血管内皮中的水解酶（SEH） VCI。我们还观察到小鼠，高脂饮食（HFD）诱导的2型糖尿病会导致类似的增加在脑血管中。我们的初步数据表明，具有本构过表达的转基因小鼠内皮（TIE2-HSEH）中的人Seh的空间记忆（Morris Water Maze）受损，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是否上调会损害通过通过脑组织浸润介导的神经炎症机制的认知单核细胞衍生的巨噬细胞。研究还将确定SEH内皮特异性缺失的小鼠是否（TIE2-CRE/FLOXED-SEH）受到HFD诱导的神经元丧失，神经炎症和认知的保护损害。最后，我们将使用两种不同的疗法，一种旨在抑制SEH，一种旨在防止单核细胞/巨噬细胞浸润，以确定这些药物是否可以预防（当认知之前给出时下降）或反向（在认知障碍后给出）TIE2-HSEH小鼠与年龄相关的认知缺陷和HFD上的野生型小鼠。