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Adiponectin on cerebrovascular regulation in vascular cognitive impairment and dementia (VCID)

脂联素对血管性认知障碍和痴呆 (VCID) 的脑血管调节作用

基本信息

批准号：
10542359
负责人：
Jun Chen
金额：
$ 39.75万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10542359
关键词：
3-Dimensional Accounting Adipocytes Agonist Alzheimer&apos s Disease Attention Attenuated Blood - brain barrier anatomy Blood Circulation Blood Vessels Blood brain barrier dysfunction Brain Carotid Stenosis Cerebral cortex Cerebrospinal Fluid Cerebrovascular Circulation Cerebrovascular Disorders Chronic Cognitive Cognitive deficits Common carotid artery Data Dementia Development Diffusion Magnetic Resonance Imaging Disease Electrophysiology (science)Endothelial Cells Endothelium Etiology Event Exhibits Extravasation Functional disorder Future Glucose Heat-Shock Proteins 90 Homeostasis Impaired cognition In Vitro Incidence Inflammation Inflammatory Inflammatory Response Injury Intraperitoneal Injections Knock-out Knockout Mice Lesion Meta-Analysis Metabolic Metabolic dysfunction Modeling Mood Disorders Mus NOS3 gene Nervous System Physiology Nitric Oxide North America Outcome Oxygen Pathogenesis Pathologic Pathology Patients Peripheral Plasma Play Population Predisposition Preparation Production Regimen Regulation Reporting Role Stroke System Testing Therapeutic Effect Treatment Protocols Vascular Dementia Vascular blood supply Wild Type Mouse adipokines adiponectin aged arteriole blood-brain barrier penetration brain cell cerebral hypoperfusion cerebrovascular chemokine cognitive function cytokine deprivation effective therapy endothelial dysfunction fatty acid oxidation glucose metabolism hypoperfusion immune cell infiltrate improved in vivo in vivo Model mouse model neuroinflammation novel novel strategies novel therapeutics preservation prophylactic receptor sex single-cell RNA sequencing small molecule therapeutic target vascular cognitive impairment and dementia white matter white matter damage white matter injury young adult

项目摘要

Vascular insufficiency underlies the pathogenesis of vascular cognitive impairment and dementia (VCID). The pathological events in VCID involves crosstalk between the CNS and peripheral metabolic regulation, yet the details in bridging two compartments are underexplored. To fill this gap, the present proposal focuses on the impact of the adiponectin in the progression of VCID. Adiponectin is an adipokine mainly produced by adipocytes and secreted into the bloodstream, regulating glucose metabolism and fatty acid oxidation. Using a mouse model of chronic cerebral hypoperfusion-induced VCID by asymmetric common carotid artery stenosis (ACAS), we found that adiponectin levels increased in plasma 3d to 42d after ACAS, yet were suppressed in cerebrospinal fluid at 42d after ACAS. We obtained further promising data showing that 1) Adiponectin knockout (KO) mice exhibited more prominent cognitive deficits up to 42d after ACAS, whereas administration of adipoRon, a small-molecule agonist of adiponectin receptor (adipoR), rescued long-term cognitive functions in adiponectin KO mice and attenuated cognitive deficits in wild-type mice; 2) Adiponectin KO exacerbated, while adipoRon treatment improved long-term white matter structural and functional integrity; 3) Adiponectin receptors AdipoR1/R2 were highly expressed on endothelial cells (ECs); 4) Adiponectin KO exacerbated the reduction in cortical cerebral blood flow (CBF) after ACAS; 5) AdipoRon promotes endothelial nitric oxide synthase activation in cultured EC; 6) AdipoRon reduced blood brain barrier (BBB) leakage in vivo after ACAS and protected from oxygen-glucose deprivation (OGD)-induced hyperpermeability in an in vitro BBB model. 7) AdipoRon treatment inhibited neuroinflammation after ACAS and inhibited the release of inflammatory factors from primary EC upon OGD. The current proposal will further explore the effects of adiponectin on endothelial function in ACAS, including vasoactivity, BBB integrity, and EC inflammation and will develop in vivo adipoRon regimen as a novel strategy to preserve white matter and improve cognitive function. The central hypothesis is that adiponectin ameliorates cognitive deficits and white matter injury in chronic cerebral hypoperfusion- induced VCID at least in part by enhancing endothelial-dependent vasoactivity and BBB integrity. Aim 1. Test if adiponectin improves endothelial-dependent vasoactivity and CBF by enhancing vascular production of nitric oxide following chronic cerebral hypoperfusion-induced VCID. Aim 2. Test if adiponectin inhibits endothelial inflammation and protects the BBB integrity against hypoperfusion-induced injury. Aim 3. Test if adipoRon treatment maintains white matter integrity and long-term neurological functions after ACAS in young and aged mice of both sexes.

血管功能不全是血管性认知障碍和痴呆的发病机制