The goal of this pilot study is to understand the contribution of the glycosaminoglycan hyaluronate (HA) to demyelination and gliosis in the aging central nervous system (CNS). Age-related changes in cortical white matter have been implicated in cognitive impairment. These changes include alterations in astrocytes that mimic reactive gliosis and the breakdown of myelin sheaths. In neurodegenerative conditions, glial cells overexpress the CD44 transmembrane glycoprotein, a receptor for HA. We recently found that chronic CD44 overexpression by oligodendrocytes results in increased HA and progressive demyelinating disease, while alterations in the HA-based extracellular matrix promote reactive astrogliosis. Our preliminary data suggest that many of the changes in CD44 expression and HA distribution that occur in neurodegenerative conditions also occur in the aging brain. These findings support the hypothesis that CD44 and HA accumulation are induced during the course of normal aging and may contribute to aging-related demyelination and astrogliosis. Here, we will test this hypothesis by (1) examining how HA accumulates in the aging primate and rodent CNS; and (2) testing the requirement for CD44 in promoting gliosis and related cognitive changes in the aging rodent brain. These studies will provide substantial insight into the contribution of CD44 and HA to alterations in elderly white matter, and will provide substantial preliminary data for a larger, future proposal aimed at determining how targeting HA and CD44 can reverse altered glial cell function and, ultimately, cognitive impairment.
| Cargill, Robert; Kohama, Steven G; Struve, Jaime et al. (2012) Astrocytes in aged nonhuman primate brain gray matter synthesize excess hyaluronan. Neurobiol Aging 33:830.e13-24 |
