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 项目摘要/摘要 脑淀粉样血管病（CAA）和 阿尔茨海默氏病（AD）尚不清楚，BBB功能障碍的机制仍有待阐明。 BBB唯一性由内皮细胞给出，由神经血管单元的细胞支持。改变 在BBB - 内皮屏障功能中，可能导致血管渗透性增加，血浆渗出 大脑中成分，炎症反应和神经元毒性。在CAA中，淀粉样蛋白β（Aβ）积累 在脑微血管上已显示出诱导血管通透性和BBB破坏。最近的发现 我们的实验室首次证明5-羟色胺亚型3受体（5HT3R）在 尸体人类脑组织和原代内皮细胞的脑血管内皮细胞从 野生型小鼠和TGSWDI，CAA和AD的小鼠模型。此外，我们的发现证明有所增加 CAA中内皮-5HT3R的表达；并用特定的5HT3R拮抗剂阻断内皮-5HT3R 显着增强了BBB功能。在CAA中，森林山的影响和机制增加 BBB功能上的5HT3R尚不清楚。我们的长期目标是阐明BBB功能障碍的机制 CAA和与广告相关的疾病，并确定用于恢复其功能的治疗发展靶标。这 该提案的目的是阐明CAA和AD中5HT3R和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表达的增加会破坏BBB功能。这 理由是了解Aβ诱导的内皮-5HT3R在BBB功能障碍中的影响 针对ADRD的热干预措施的新目标。中心假设将通过追求两个来检验 具体目的：1）调查死后人脑内皮-5HT3R表达的变化 组织； 2）研究内皮-5HT3R表达/功能对BBB紧密度的变化的影响 以及使用遗传和药物调制方法的功能。结论，我们希望 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，因为他们将确定CAA中BBB功能障碍的新见解， 广告并制定新的治疗干预策略。未来的计划将在R01中扩展这项工作 用于研究5HT3R诱导的BBB-末端表达的分子机制的应用 CAA和AD，并开发和测试可以恢复BBB功能的药物。