Online Archive of University of Virginia Scholarship
Evidence for oligodendrocyte progenitor cell heterogeneity and their role in Alzheimer's disease195 views
Author
Beiter, Rebecca, Neuroscience - School of Medicine, University of Virginia0000-0002-0756-6037
Advisors
Gaultier, Alban, MD-NESC Neuroscience, University of Virginia
Abstract
White matter loss has been described as a common occurrence in Alzheimer’s disease (AD) patients for multiple decades. However, it remains unclear why oligodendrocyte progenitor cells (OPCs) fail to repair myelin deficits in these patients. Here, we show that clusterin, a risk factor for late-onset AD, is produced by OPCs and inhibits their differentiation into oligodendrocytes. Specifically, we demonstrate that a unique subset of OPCs produces clusterin. We show that phagocytosis of debris, including amyloid beta (Aβ) and myelin, drives the upregulation of clusterin in OPCs. We confirm, in vivo, that Aβ oligomers drive clusterin upregulation and that OPCs phagocytose Aβ. Furthermore, we show that clusterin is a potent inhibitor of OPC differentiation and prevents the production of myelin proteins. Finally, we demonstrate that clusterin inhibits OPC differentiation by significantly reducing the production of IL-9 by OPCs. Our data reveals that clusterin may be responsible for the lack of myelin repair observed in AD and is a promising therapeutic target for AD-associated cognitive decline.
Beiter, Rebecca. Evidence for oligodendrocyte progenitor cell heterogeneity and their role in Alzheimer's disease. University of Virginia, Neuroscience - School of Medicine, PHD (Doctor of Philosophy), 2022-08-15, https://doi.org/10.18130/7aja-as23.