Investigating the role of astrocyte specific NFIA during initiation and progression of AD pathogenesis

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Project Summary / 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 NFIA contributes to astrocyte-mediated regulation of brain circuits and memory in the brain, and it was highly increased in reactive astrocytes in the AD mouse brain. 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 NFIA regulates functions of astrocytes and reactive astrocytes. Here, using a newly generated animal model, in preliminary data, we found that gain or- / loss of- NFIA in astrocytes showed decreasing/increasing of A accumulation in AD mouse brain. These results lead us to the hypothesis that astrocytic NFIA has a role in astrocytes and reactive astrocytes for AD pathogenesis. To test this, we proposed experiments to confirm NFIA expression in the human AD brain and to analyze AD pathogenesis in AD mouse brain with behavioral alteration by time different NFIA manipulation in astrocytes (Aim 1). We next asked how NFIA contributes to the alteration of astrocyte function for AD pathogenesis since NFIA regulates astrocyte core properties. To test this, we proposed experiments to confirm alteration of A production / clearance ability of astrocytes, astrocytes calcium activation and astrocyte mediated neurotransmission by time different NFIA manipulation (Aim 2). Preliminary data revealed that NFIA regulated AD-related genes in hippocampal astrocytes. Therefore, we will use RNA-seq and ChIP-seq to investigate the NFIA-regulated candidates and networks for AD pathogenesis in astrocytes and reactive astrocytes. Furthermore, we will validate the candidates using gene manipulating methods in astrocytes and reactive astrocytes from the initiation to progression stages of AD pathogenesis (Aim 3). These results will reveal whether and how astrocytic NFIA contributes to AD pathogenesis and how astrocytes contribute to AD pathogenesis from initiation to progression. For my career development, these studies will provide training in the glia-AD relationship under my mentor Dr. Deneen (expert in astrocyte biology) and co-mentor Dr. Jankowsky (expert in Alzheimer's disease) at Baylor College of Medicine. Since astrocytes are intimately connected with neurons and are dysregulated in all neurological disorders, this proposal aims to uncover how astrocytes contribute to neurodegenerative disease development. Towards this goal, the proposed research will apply new approaches to astrocyte biology to delineate genetic and functional mechanisms involved in the progression of neurodegeneration.