Defining Roles for Astrocyte Subpopulations in the Aging Brain

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Abstract Astrocytes are the most abundant and diverse glial cells in the adult brain, comprising 70% of the glial constituency. Astrocytes perform essential tasks for normal brain function and contribute to various neurological disorders, including neurodegenerative diseases such as Alzheimer's disease (AD). However, their role in health and disease remains a mystery. Recently, we found that Sox9 contributes to astrocyte-mediated regulation of brain circuits, and demonstrated increased expression in reactive astrocytes in the human AD samples. Furthermore, in preliminary data presented in the parent grant we found that Sox9 has an aging- specific role in maintaining the functional integrity of hippocampal astrocytes. Together these observation prompted us to further investigate whether Sox9 also plays a role in AD pathogenesis. Critically, although the reactive astrocytes are closely associated with degenerating neurons across multiple brain regions in patients with AD, it is largely unknown how astrocytes contribute to the initiation and progression of AD and how astrocytic Sox9 regulates functions of astrocytes and reactive astrocytes in this context also remains undefined. In this proposal, we will use newly generated animal models that enable us to overexpress or knockout Sox9 selectively in astrocytes, during different stages of AD disease progression. Our preliminary studies with these models demonstrated that astrocytic Sox9 plays an essential role in Ab plaque accumulation at the onset of AD progression, where knockout of Sox9 enhanced Ab plaque formation, while its overexpression suppressed Ab plaque formation. These results lead us to the hypothesis that astrocytic Sox9 plays a central role in astrocytes and reactive astrocytes during AD pathogenesis. To test this, we propose experiments to confirm Sox9 expression in the human AD brain and to use stage specific manipulations of Sox9 during early- and middle- stages of disease progression to determine how it impacts AD pathogenesis and associated behavioral- and circuit- levels alterations (Aim 1). To understand how Sox9 impacts astrocytes associated with AD pathogenesis, we will examine a host of core astrocytic properties including morphology, Ca2+ activity, and interactions with neurons in our stage- specific, overexpression and knockout models (Aim 2). In sum, our preliminary observations suggests that astrocytic-Sox9 contributes to AD pathogenesis, warranting further investigation into when it exerts these effects and how it impacts astrocyte physiology across AD progression.