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.

抽象的： 阿尔茨海默病 (AD) 是一种毁灭性的神经退行性疾病，影响超过 600 万人 尽管多年来人们对 Aβ 和 Tau 在 AD 病理学中的作用进行了积极的研究，但我们的 对这种疾病的了解仍然不完整，患者群体仍然没有有效的治疗方法 解决疾病症状的治疗选择。 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学原因。 在阿尔茨海默氏病患者中发现，髓磷脂破坏是导致阿尔茨海默病的一个关键事件 AD 中认知能力下降的原因仍不清楚。 在整个成年期产生新的产生髓磷脂的少突胶质细胞，但无法修复 AD 中的髓磷脂。 Clusterin，也称为 ApoJ，是 CLU 中的一种分泌型多功能蛋白，存在于 36% 的细胞中。 此外，携带该 SNP 的年轻健康成年人是晚发 AD 的一个重要危险因素。 白质完整性较低，可能表明髓磷脂水平增加。 尽管有强有力的证据表明，AD 患者的大脑中存在着这种现象，并且与认知能力下降有关。 Clusterin、髓磷脂和 AD 之间的联系，Clusterin 在 OPC 和髓鞘形成中的作用 AD从未被研究过。 我们提案的优势来自于 OPC 在 AD 和小鼠中表达 Clusterin 的发现 该提案的基础是我们的初步工作表明 Clusterin 抑制 在这一证据的指导下，我们假设 Clusterin 发挥作用。 一种通过阻止 OPC 分化为髓鞘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 Clusterin 表达和抑制的机制 OPC 分化；2：评估病理性 Clusterin 表达对髓鞘形成、学习和发育的影响 阿尔茨海默病动物模型中的记忆；3：检查少突胶质细胞之间的联系 谱系、Clusterin 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。 Clusterin 在 OPC 中的作用以及 Clusterin 对 OPC 分化影响的信号通路。 第二个目标，我们建议利用 Clusterin 的遗传和治疗抑制来增强髓磷脂修复 AD 临床前模型的第三个目标包括精确量化 OPC、少突胶质细胞和 Clusterin。 在正常人类衰老和 AD 患者中表达。 我们的提议很新颖，因为我们将探索 Clusterin 和髓磷脂在 AD 病理学中的作用，这是一条途径 我们的建议很重要，因为这些研究将提供新的治疗方法。 向社区介绍少突胶质细胞对 AD 病理学的贡献。