5HT3 receptors and blood-brain barrier dysfunction in ADRD

ADRD 中的 5HT3 受体和血脑屏障功能障碍

• 批准号: 10575480
• 负责人: Amal F Khalil Kaddoumi
• 金额: $ 39.81万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10575480
• 关键词: Adherens Junction; Age; Agonist; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-Protein; Amyloidosis; Astrocytes; Autopsy; Biochemical; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Brain; Brain region; Calcium; Carrier Proteins; Cell Communication; Cell Separation; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular system; Characteristics; Clinical; Crossbreeding; Dementia; Development; Endothelial Cells; Endothelium; Extravasation; Frequencies; Functional disorder; Future; Genetic; Goals; Granisetron; Grant; Health; Health Care Costs; Homeostasis; Human; In Vitro; Inflammatory Response; Laboratories; Lead; Mediating; Memory; Modeling; Molecular; Mus; Nerve Degeneration; Neurons; Outcome; Pathologic; Pathway interactions; Pattern; Pericytes; Permeability; Pharmaceutical Preparations; Pharmacological Treatment; Plasma; Public Health; Receptor Down-Regulation; Reporting; Role; Serotonin; Serotonin Receptors 5-HT-3; Severities; Supporting Cell; Testing; Therapeutic Intervention; Tight Junctions; Time; Vascular Diseases; Vascular Permeabilities; Wild Type Mouse; Work; abeta accumulation; abeta toxicity; antagonist; blood-brain barrier disruption; blood-brain barrier function; brain tissue; cerebral microvasculature; cerebrovascular; high throughput screening; improved; in vivo; insight; mouse model; neurotoxicity; neurovascular unit; new therapeutic target; novel therapeutic intervention; pharmacologic; preservation; receptor; receptor downregulation; receptor expression; receptor function; targeted treatment; therapeutic development; therapeutic evaluation

5HT3 receptors and blood-brain barrier dysfunction in ADRD PROJECT SUMMARY/ABSTRACT The exact causes for blood-brain barrier (BBB) dysfunction in cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD) is not well known, and the mechanisms of BBB dysfunction remain to be elucidated. The BBB uniqueness is given by the endothelial cells, supported by cells of the neurovascular unit. Alterations in the BBB-endothelium barrier function may lead to increased vascular permeability, extravasation of plasma components, inflammatory responses, and neuronal toxicity in the brain. In CAA, amyloid-β (Aβ) accumulation on brain microvessels has been shown to induce vascular permeability and BBB disruption. Recent findings from our laboratory demonstrated for the first time that serotonin subtype 3 receptor (5HT3R) is expressed in cerebrovascular endothelial cells of postmortem human brain tissues and primary endothelial cells isolated from wild-type mice and TgSwDI, a mouse model of CAA and AD. In addition, our findings demonstrated increased expression of endothelium-5HT3R in CAA; and blocking endothelium-5HT3R with a specific 5HT3R antagonist significantly enhanced the BBB function. In CAA, the impact and the mechanism of increased endothelium- 5HT3R on BBB function are unknown. Our long-term goal is to elucidate the mechanism of BBB dysfunction in CAA and AD-related disorders and identify targets for therapeutics development to restore its function. The objective of this proposal is to clarify the relationship between 5HT3R and BBB dysfunction in CAA and AD. Our central hypothesis is that Aβ-mediated increase of endothelium-5HT3R expression disrupts BBB function. The rationale is that understanding the impact of Aβ-induced endothelium-5HT3R in BBB dysfunction could offer novel targets for therapeutic interventions against ADRD. The central hypothesis will be tested by pursuing two specific aims: 1) Investigate changes in the expression of endothelium-5HT3R in postmortem human brain tissues; and 2) Investigate the effect of changes in endothelium-5HT3R expression/function on the BBB tightness and function using genetic and pharmacological modulation approaches. Upon conclusion, we expect to demonstrate an association between endothelium-5HT3R expression, BBB dysfunction, and CAA. The results will have a significant positive impact because they will identify new insights into BBB dysfunction in CAA and AD and develop new strategies for therapeutic interventions. Future plans are to extend this work in an R01 application to investigate the molecular mechanism(s) for 5HT3R induced expression in the BBB-endothelium in CAA and AD and to develop and test therapeutic drugs that could restore BBB function.

5HT3受体与ADRD患者血脑屏障功能障碍 项目摘要/摘要 脑淀粉样血管病患者血脑屏障(BBB)功能障碍的确切原因 阿尔茨海默病(AD)的发病机制尚不清楚，血脑屏障功能障碍的机制尚不清楚。 血脑屏障的独特性是由血管内皮细胞提供的，由神经血管单位的细胞支持。改建 在血脑屏障-内皮屏障功能可能导致血管通透性增加、血浆外渗 大脑中的成分、炎症反应和神经元毒性。在CAA中，淀粉样蛋白β(Aβ)积聚 对脑微血管的影响已被证明可以诱导血管通透性和血脑屏障的破坏。最新发现来自 我们的实验室首次证实5-羟色胺亚型3受体(5HT3R)在 人死后脑组织中的脑血管内皮细胞和分离的原代内皮细胞 野生型小鼠和CAA、AD小鼠模型TgSwDI。此外，我们的研究结果显示， 血管内皮-5HT3R在CAA中的表达及特异性5HT3R拮抗剂的阻断作用 显著增强血脑屏障功能。在CAA中，内皮细胞增加的影响及其机制 5HT3R对BBB功能的影响尚不清楚。我们的长期目标是阐明血脑屏障功能障碍的机制。 CAA和AD相关疾病，并确定治疗开发的目标，以恢复其功能。这个 本研究的目的是阐明5HT3R与CAA和AD患者血脑屏障功能障碍的关系。我们的 中心假说是β介导的内皮-5HT3R表达增加扰乱了血脑屏障功能。这个 基本原理是，了解β诱导的内皮-5HT3R在血脑屏障功能障碍中的影响可能会提供 针对ADRD的治疗干预的新目标。核心假说将通过追求两个 具体目的：1)研究死后人脑组织内皮细胞-5HT3R的表达变化 2)研究内皮-5HT3R表达/功能变化对血脑屏障密封性的影响 并使用遗传和药物调节方法发挥作用。在结束时，我们预计 证明内皮-5HT3R表达、血脑屏障功能障碍和CAA之间存在关联。结果是 将产生重大的积极影响，因为他们将确定对CAA和 广告和制定新的治疗干预策略。未来的计划是将这项工作扩展到R01 S在5HT3R诱导大鼠血脑屏障内皮细胞表达分子机制研究中的应用 CAA和AD，并开发和测试可恢复血脑屏障功能的治疗药物。