Understanding the impact of Clusterin on the oligodendrocyte lineage in AD

了解 Clusterin 对 AD 少突胶质细胞谱系的影响

• 批准号: 10539074
• 负责人: Alban P Gaultier
• 金额: $ 162.15万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539074
• 关键词: Address; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Amyloid beta-Protein; Animal Model; Apoptosis; Astrocytes; Axon; Brain; Caregivers; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Clinical; Communities; Complement; Data; Disease; Event; Foundations; Genes; Genetic; Health system; Healthcare; Human; Impaired cognition; In Vitro; Interleukin-9; Knowledge; Late Onset Alzheimer Disease; Lead; Learning; Light; Mediating; Memory; Multiple Sclerosis; Mus; Myelin; Myelin Proteins; Nerve Degeneration; Neurodegenerative Disorders; Oligodendroglia; Outcome; Pathologic; Pathology; Patients; Plasma; Population; Pre-Clinical Model; Primary Cell Cultures; Production; Proteins; Reporting; Research; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Source; Suggestion; Supplementation; T-Lymphocyte; Therapeutic; Up-Regulation; Work; base; cytokine; gray matter; improved; in vivo; inhibitor; interleukin 9 receptor; mouse model; myelination; neuroprotection; novel; novel therapeutic intervention; oligodendrocyte lineage; oligodendrocyte progenitor; overexpression; patient population; prevent; receptor expression; remyelination; repaired; risk variant; single-cell RNA sequencing; stem cells; sulfated glycoprotein 2; tau Proteins; therapeutically effective; white matter

Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disease that impacts more than 6 million Americans. Despite years of active research centered on the role of Aβ and Tau in AD pathology, our understanding of the disease remains incomplete and the patient population remains without effective therapeutic options to tackle disease symptomology. In recent years, increasing amounts of data have pointed to myelin disruption as a significant pathological finding in Alzheimer’s disease patients, with the concept that myelin disruption is a key event that contributes to cognitive decline in AD. It remains unclear why oligodendrocyte progenitor cells (OPCs), a population able to give rise to new myelin-producing oligodendrocytes throughout adulthood, fail to repair myelin in AD. Clusterin, also known as ApoJ, is a secreted multifunctional protein. A SNP in CLU, present in 36% of the population, is a significant risk factor for late onset AD. Additionally, young healthy adults carrying this SNP present with lower white matter integrity, possibly suggestive of myelin reduction. Clusterin levels are increased in the brain of AD patients and correlate with cognitive decline. Despite strong evidence pointing toward a connection between Clusterin, myelin, and AD, the role of Clusterin in OPCs and myelination in the context of AD has never been studied. The strength of our proposal comes from the discovery that OPCs express Clusterin in AD and a mouse model of AD. The foundation of this proposal is our preliminary work showing that Clusterin inhibits the differentiation of OPCs into oligodendrocytes. Guided by this evidence, our hypothesis that Clusterin acts as an inhibitor of myelin repair by preventing OPC differentiation into myelinating oligodendrocytes will be addressed by pursuing three specific aims: 1: Determine the mechanisms of Clusterin expression and inhibition of OPC differentiation; 2: Assess the impact of pathological Clusterin expression on myelination, learning and memory in an animal model of Alzheimer’s Disease; 3: Examine the connection between the oligodendrocyte lineage, Clusterin and human AD pathology. Under the first aim, we will discover the factors that drive expression of Clusterin in OPCs and the signaling pathways involved in Clusterin’s impact on OPC differentiation. In the second aim, we propose to use genetic and therapeutic inhibition of Clusterin to enhance myelin repair in a preclinical model of AD. The third aim consists of precisely quantifying OPCs, oligodendrocytes, and Clusterin expression in normal human aging and AD patients. Our proposal is novel because we will explore the role of Clusterin and myelin in AD pathology, an avenue that could lead to new treatments for AD. Our proposal is significant because these studies will provide new knowledge to the community about the contribution of oligodendrocytes to AD pathology.

摘要： 阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，影响超过600万人 美国人尽管多年来积极的研究集中在Aβ和Tau在AD病理学中的作用，我们的研究结果表明， 对疾病的了解仍然不完全，患者人群仍然没有有效的治疗方法。 治疗方案，以解决疾病病理学。 近年来，越来越多的数据表明髓磷脂破坏是一种重要的病理性损伤。 在阿尔茨海默病患者中发现，髓磷脂破坏是导致阿尔茨海默病的关键事件， 认知能力下降目前还不清楚为什么少突胶质祖细胞（OPCs），一个能够 在整个成年期产生新的产生髓鞘的少突胶质细胞，在AD中不能修复髓鞘。 ApoJ是一种分泌型多功能蛋白质。CLU中的SNP，存在于36%的 是晚发性AD的重要危险因素。此外，携带这种SNP的年轻健康成年人 存在较低的白色物质完整性，可能提示髓鞘减少。胆固醇水平升高 在AD患者的大脑中，并与认知能力下降相关。尽管有强有力的证据表明 髓鞘和AD之间的联系，髓鞘在OPCs和髓鞘形成中的作用， AD从未被研究过。 我们的建议的力量来自于发现OPCs在AD和小鼠中表达白细胞介素 AD模型这项建议的基础是我们的初步工作，表明阿糖胞苷抑制 OPCs向少突胶质细胞的分化。在此证据的指导下，我们的假设是， 通过阻止OPC分化成髓鞘形成少突胶质细胞的髓鞘修复抑制剂， 通过追求三个具体目标来解决：1：确定Escherin表达和抑制的机制 2：评估病理性髓鞘素表达对髓鞘形成、学习和预后的影响。 阿尔茨海默病动物模型的记忆; 3：检查少突胶质细胞之间的联系 谱系、白细胞介素和人类AD病理学。在第一个目标下，我们将发现驱动表达的因素 OPCs中的白藜芦醇苷以及白藜芦醇苷对OPCs分化的影响所涉及的信号通路。在 第二个目标，我们建议使用遗传和治疗抑制髓鞘，以加强髓鞘修复， AD的临床前模型。第三个目标是精确定量OPCs、少突胶质细胞和白细胞介素 在正常人衰老和AD患者中的表达。 我们的建议是新颖的，因为我们将探索在AD病理学，一个途径， 这可能会导致新的治疗方法。我们的建议意义重大，因为这些研究将提供新的 向社区宣传少突胶质细胞对AD病理学的贡献。