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

• 批准号: 10338744
• 负责人: Tuo Yang
• 金额: $ 39.44万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/10338744
• 关键词: 3-Dimensional; Accounting; Adipocytes; Agonist; Alzheimer' s Disease; Attention; Attenuated; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Carotid Stenosis; Cells; 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; Immune; Impaired cognition; In Vitro; Incidence; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Intraperitoneal Injections; Knock-out; Knockout Mice; Lesion; Meta-Analysis; Metabolic; Metabolic dysfunction; Methods; Modeling; Mood Disorders; Mus; NOS3 gene; Nervous System Physiology; Nitric Oxide; North America; Outcome; Oxygen; Pathogenesis; Pathologic; Pathology; Patients; Peripheral; Plasma; Play; Population; 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; brain cell; cerebral hypoperfusion; cerebrovascular; chemokine; cognitive function; cytokine; deprivation; effective therapy; endothelial dysfunction; fatty acid oxidation; glucose metabolism; hypoperfusion; 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

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 （VCID）。VCID中的病理事件涉及CNS和外周之间的串扰 代谢调节，但在桥接两个隔间的细节是探索不足。填补这一 差距，目前的建议集中在脂联素在VCID的进展的影响。 脂联素是一种主要由脂肪细胞产生并分泌到血液中的脂肪因子， 调节葡萄糖代谢和脂肪酸氧化。使用慢性脑缺血小鼠模型， 低灌注诱导的VCID不对称颈总动脉狭窄（ACAS），我们发现 ACAS后3~42d血浆脂联素水平升高，而ACAS后42d血浆脂联素水平降低， ACAS后42d脑脊液。我们获得了进一步有希望的数据，表明1） 脂联素敲除（KO）小鼠在ACAS后42天表现出更显著的认知缺陷， 而给予adipoRon，一种脂联素受体（adipoR）的小分子激动剂， 挽救了脂联素基因敲除小鼠的长期认知功能， 野生型小鼠; 2）脂联素KO加重，而adipoRon治疗改善了长期 白色物质结构和功能的完整性; 3）脂联素受体AdipoR1/R2高度表达， 4）脂联素KO加重了内皮细胞（EC）上表达的脂联素的减少， ACAS后的脑血流量（CBF）; 5）AdipoRon促进内皮型一氧化氮合酶 6）AdipoRon在培养的EC中激活后减少体内血脑屏障（BBB）渗漏。 ACAS和保护免受氧-葡萄糖剥夺（OGD）诱导的高渗透性在一个细胞中， 体外血脑屏障模型7)AdipoRon治疗可抑制ACAS后的神经炎症， OGD时原代EC释放炎症因子。目前的建议将进一步 探讨脂联素对ACAS中内皮功能的影响，包括血管活性、血脑屏障 完整性和EC炎症，并将在体内开发adipoRon方案作为一种新的策略， 保护白色物质并改善认知功能。核心假设是脂联素 改善慢性脑灌注不足的认知缺陷和白色物质损伤， 至少部分通过增强内皮依赖性血管活性和BBB诱导VCID 完整目标1.检测脂联素是否改善内皮依赖性血管活性和CBF， 增加慢性脑低灌注诱导的血管生成一氧化氮 VCID。目标2.检测脂联素是否抑制内皮炎症并保护血脑屏障完整性 防止低灌注引起的损伤。目标3.测试adipoRon治疗是否保持白色物质 完整性和ACAS后的长期神经功能在两种性别的年轻和老年小鼠。