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Neuroinflammatory Mechanisms of Vascular Cognitive Impairment

血管性认知障碍的神经炎症机制

基本信息

批准号：
10753185
负责人：
Nabil J Alkayed
金额：
$ 165.9万
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 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10753185
关键词：
Age Age Months Aging Anti-Inflammatory Agents Autopsy B-Lymphocytes Biological Availability Blood - brain barrier anatomy Blood Preservation Blood Vessels Blood brain barrier dysfunction Brain Cells Cerebrovascular Circulation Cholesterol Chronic Clinical Cognitive Cognitive deficits Dementia Dependence Development Diabetes Mellitus Dyslipidemias Elderly Emotional Encephalitis Endothelial Cells Endothelium Epidemiology Epoxide hydrolase Exhibits Family Female Financial Hardship Flow Cytometry Healthcare Systems High Fat Diet Histopathology Human Hyperlipidemia Hypertension Immune Immunohistochemistry Impaired cognition Infiltration Inflammatory Invaded Leucocytic infiltrate Leukocytes Life Link Lipids LoxP-flanked allele Magnetic Resonance Imaging Maps Measurement Metabolic Metabolic Diseases Metabolic syndrome Microvascular Dysfunction Modeling Mus Neurocognitive Deficit Neutrophil Infiltration Obesity Patients Peripheral Process Property Public Health Recording of previous events Reporter Risk Risk Factors Role Severities Sex Differences Signaling Molecule Testing Therapeutic Time Up-Regulation Vascular Cognitive Impairment Vascular Endothelium Ventricular Wild Type Mouse age related aged blood-brain barrier crossing blood-brain barrier disruption blood-brain barrier permeabilization brain parenchyma brain tissue cardiovascular risk factor cerebral atrophy cerebrovascular cognitive testing enzyme activity glial activation human old age (65+)immune cell infiltrate inhibitor innovation male middle age morris water maze neuroinflammation novel object recognition overexpression pharmacologic prevent response secondary outcome single-cell RNA sequencing translational study treatment effect white matter damage

项目摘要

ABSTRACT Aging-related dementia is a major public health concern that places an enormous emotional, physical, and financial stress on patients, their families and health-care systems. Clinical and epidemiological evidence suggests that the presence of vascular and metabolic risk factors, such as obesity, diabetes, dyslipidemia and hypertension, collectively known as the metabolic syndrome (MetS), during midlife increases the risk for and severity of dementia in late-life. The proposed studies will use the chronic high-fat diet (HFD) model of MetS in mice to investigate the mechanism and age-dependency of MetS-related cognitive dysfunction (MetSCD). Our observations made in postmortem human brain with a history of dementia and in brains of HFD-fed mice suggest that MetS increases the expression and activity of the enzyme soluble epoxide hydrolase (sEH) in brain microvascular endothelium, leading to reduced bioavailability of its substrate epoxyeicosatrienoates (EETs), which have anti-inflammatory properties. Reduced endothelial EETs predisposes to endothelial cell activation, peripheral immune cell infiltration into brain parenchyma, neuroinflammation and cognitive dysfunction. In support of a causal link between sEH upregulation, neuroinflammation and cognitive impairment, mice with endothelial overexpression of human sEH exhibit age-dependent neuroinflammation and cognitive deficit, while pharmacological inhibition of sEH protects against HFD-induced neuroinflammation and cognitive impairment. We will test the hypothesis that MetS contributes to late-life cognitive dysfunction via the infiltration of peripheral immune cells and progressive neuroinflammation. Aim 1 will use male and female wild-type (WT) mice and mice with endothelial-specific deletion of sEH, on standard (STD) or high-fat diet (HFD), to determine the role of endothelial sEH in MetSCD at 12 and 24 months of age. Aim 2 will use flow cytometry, immunohistochemistry (IHC) and single-cell RNAseq (scRNAseq) to determine if HFD induces an age- dependent neuroinflammatory response characterized by early infiltration of neutrophils and delayed infiltration of T and B lymphocytes. We will use immune cell reporter mice (Fgd5-CreERT2;Ai9) to confirm the peripheral origin of leukocytes, characterize the time course of immune cell invasion, and determine if endothelial-specific deletion of sEH prevents immune cell infiltration into the brain of mice on HFD. Aim 3 will determine if sEH inhibitors t-AUCB (brain-penetrant) and GSK2256294 (does not cross the blood-brain barrier, BBB) protect against neurocognitive impairment in mice on chronic HFD. We will also determine if there are sex differences in treatment effects. The proposed studies are highly translational, and will advance understanding of mechanisms and age-dependency MetSCD. The endothelial origin of age-dependent immune cell infiltration in MetSC is novel, and so is the use of scRNAseq and immune cell fate mapping using Fgd5-CreERT2; Ai9 mice.

摘要