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： 阿尔茨海默氏病（AD）是一种破坏性的神经退行性疾病，影响超过600万 美国人。尽管多年的积极研究集中于Aβ和TAU在AD病理学中的作用，但我们 对疾病的理解仍然不完整，患者人数仍然没有有效 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 在阿尔茨海默氏病患者中发现，髓磷脂破坏是一个有助于的关键事件 AD认知能力下降。目前尚不清楚为什么少突胶质细胞祖细胞（OPC），人群可以 引起整个成年期新的产生髓磷脂的少突胶质细胞，无法修复AD中的髓磷脂。 簇蛋白，也称为apoj，是一种分泌的多功能蛋白。 CLU中的SNP，以36％的形式存在 人口是延迟发作广告的重要危险因素。此外，携带此SNP的年轻健康成年人 具有较低的白质完整性，可能暗示减少髓鞘。簇素水平增加 在AD患者的大脑中，与认知能力下降相关。尽管有强烈的证据表明 簇素，髓磷脂和AD之间的联系，簇素在OPC中的作用和在髓鞘中的作用 广告从未研究过。 我们的提议的优势来自于发现OPC在AD和鼠标中表达簇素的发现 AD模型。该提案的基础是我们的初步工作，表明簇素抑制了 OPC分化为少突胶质细胞。在这一证据的指导下，我们的假设是簇素起作用 通过防止OPC分化为髓生成少突胶质细胞，髓磷脂修复的抑制剂将是 通过追求三个特定目标来解决：1：确定簇蛋白表达和抑制的机制 OPC分化； 2：评估病理簇蛋白表达对髓鞘化，学习和 在阿尔茨海默氏病动物模型中记忆； 3：检查少突胶质细胞之间的联系 谱系，簇和人类AD病理学。在第一个目标下，我们将发现推动表达的因素 OPC中的簇蛋白和簇素对OPC分化的影响所涉及的信号通路。在 第二个目的，我们建议使用簇素的遗传和治疗性抑制来增强髓磷脂修复 AD的临床前模型。第三个目标包括精确量化OPC，少突胶质细胞和簇蛋白 正常的人类衰老和AD患者的表达。 我们的建议是新颖的，因为我们将探索簇素和髓磷脂在AD病理学中的作用， 这可能会导致广告的新治疗方法。我们的建议很重要，因为这些研究将提供新的 了解社区关于少突胶质细胞对AD病理学的贡献的知识。