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: 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
• 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' 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

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的基础 （VCID）。 VCID 的病理事件涉及中枢神经系统和外周神经系统之间的串扰 代谢调节，但桥接两个区室的细节尚未得到充分探索。为了填补这个 鉴于此，本提案重点关注脂联素对 VCID 进展的影响。 脂联素是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。使用慢性脑病小鼠模型 我们发现，不对称颈总动脉狭窄（ACAS）引起的低灌注引起的 VCID ACAS 后 3 天至 42 天血浆中脂联素水平升高，但在 ACAS后42天的脑脊液。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 天表现出更明显的认知缺陷， 而施用 adipoRon（脂联素受体 (adipoR) 的小分子激动剂）， 挽救了脂联素 KO 小鼠的长期认知功能并减轻了认知缺陷 野生型小鼠； 2) Adiponectin KO 加剧，而 adipoRon 治疗长期改善 白质结构和功能完整性； 3) 脂联素受体 AdipoR1/R2 高度 在内皮细胞 (EC) 上表达； 4）脂联素KO加剧了皮质的减少 ACAS后脑血流量（CBF）； 5) AdipoRon 促进内皮一氧化氮合酶 培养 EC 中的激活； 6) AdipoRon 减少体内血脑屏障 (BBB) 渗漏 ACAS 并防止缺氧葡萄糖 (OGD) 引起的高渗透性 体外BBB模型。 7) AdipoRon 治疗抑制 ACAS 后的神经炎症并抑制 OGD 后原发性 EC 释放炎症因子。目前的提案将进一步 探讨脂联素对 ACAS 内皮功能的影响，包括血管活性、BBB 完整性和 EC 炎症，并将开发体内 adipoRon 方案作为一种新策略 保护白质并改善认知功能。中心假设是脂联素 改善慢性脑灌注不足的认知缺陷和白质损伤 至少部分通过增强内皮依赖性血管活性和 BBB 诱导 VCID 正直。目标 1. 测试脂联素是否通过以下方式改善内皮依赖性血管活性和 CBF： 增强慢性脑灌注不足引起的血管一氧化氮的产生 VCID。目标 2. 测试脂联素是否抑制内皮炎症并保护 BBB 完整性 对抗低灌注引起的损伤。目标 3. 测试 adipoRon 治疗是否维持白质 ACAS 后年轻和老年小鼠的完整性和长期神经功能。