Understanding the impact of Clusterin on the oligodendrocyte lineage in AD

文摘:

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.