Understanding the impact of Clusterin on the oligodendrocyte lineage in AD

摘要： 阿尔茨海默病是一种毁灭性的神经退行性疾病，影响着600多万人 美国人。尽管多年来积极的研究集中在Aβ和Tau在AD病理中的作用，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 针对疾病症状的治疗选择。 近年来，越来越多的数据表明，髓鞘破坏是一种重要的病理现象。 在阿尔茨海默病患者中的发现，其概念是髓鞘破坏是导致 阿尔茨海默病的认知功能下降。目前尚不清楚为什么少突胶质细胞前体细胞(OPC)，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。 Clusterin，又称ApoJ，是一种分泌型多功能蛋白。CLU中的SNP，存在于36%的 人群是晚发性AD的重要危险因素。此外，携带这种SNP的年轻健康成年人 脑白质完整性较低，可能提示髓鞘减少。聚集素水平升高 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 聚集素、髓磷脂和AD之间的联系，聚集素在OPC中的作用和髓鞘形成 广告从未被研究过。 我们的建议的力量来自于发现OPC在AD和一只老鼠中表达Clusterin AD的模型。这一建议的基础是我们的初步工作，表明Clusterin抑制 OPC向少突胶质细胞的分化。在这一证据的指导下，我们的假设是聚集素起着 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将被 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 2：评估病理性Clusterin表达对髓鞘形成、学习和 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 血统、聚集素和人类AD病理学。在第一个目标下，我们将发现驱动表达的因素 以及Clusterin对OPC分化的影响所涉及的信号通路。在 第二个目的是，我们建议使用聚集素的遗传和治疗抑制来促进急性髓鞘损伤的髓鞘修复。 AD的临床前模型。第三个目标是精确量化OPC、少突胶质细胞和聚集素 在正常人衰老和AD患者中的表达。 我们的建议是新颖的，因为我们将探索聚集素和髓鞘在AD病理中的作用，这是一种途径 这可能会带来治疗AD的新方法。我们的建议意义重大，因为这些研究将提供新的 向社区提供有关少突胶质细胞在AD病理中的贡献的知识。

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.