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.

ADRD 中的 5HT3 受体和血脑屏障功能障碍 项目概要/摘要 脑淀粉样血管病 (CAA) 和血脑屏障 (BBB) 功能障碍的确切原因 阿尔茨海默病 (AD) 尚不为人所知，BBB 功能障碍的机制仍有待阐明。 BBB 的独特性是由内皮细胞赋予的，并由神经血管单元的细胞支持。改动 BBB-内皮屏障功能可能导致血管通透性增加、血浆外渗 成分、炎症反应和大脑神经元毒性。在 CAA 中，β 淀粉样蛋白 (Aβ) 积聚 已证明对脑微血管的作用会引起血管通透性和血脑屏障破坏。最近的发现 我们实验室首次证明血清素亚型3受体（5HT3R）在 死后人脑组织的脑血管内皮细胞和分离的原代内皮细胞 野生型小鼠和 TgSwDI（CAA 和 AD 小鼠模型）。此外，我们的研究结果表明 CAA中内皮-5HT3R的表达；并用特定的 5HT3R 拮抗剂阻断内皮细胞 5HT3R 显着增强BBB功能。在 CAA 中，内皮细胞增加的影响和机制 5HT3R对BBB的功能尚不清楚。我们的长期目标是阐明 BBB 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 该提案的目的是阐明 CAA 和 AD 中 5HT3R 与 BBB 功能障碍之间的关系。我们的 中心假设是 Aβ 介导的内皮 5HT3R 表达增加会破坏 BBB 功能。这 基本原理是了解 Aβ 诱导的内皮细胞 5HT3R 对 BBB 功能障碍的影响可以提供 ADRD 治疗干预的新靶点。中心假设将通过追求两个 具体目标：1）研究死后人脑中内皮-5HT3R表达的变化 纸巾； 2) 研究内皮-5HT3R 表达/功能的变化对 BBB 紧密度的影响 和功能使用遗传和药理学调节方法。结论结束后，我们期望 证明内皮 5HT3R 表达、BBB 功能障碍和 CAA 之间存在关联。结果 将产生重大的积极影响，因为他们将对 CAA 中的 BBB 功能障碍有新的见解， AD 并制定新的治疗干预策略。未来的计划是在 R01 中扩展这项工作 应用研究 5HT3R 诱导 BBB 内皮表达的分子机制 CAA 和 AD 并开发和测试可以恢复 BBB 功能的治疗药物。