Alexander disease (AxD) is a rare and generally fatal neurodegenerative disorder with no effective treatments. Nearly all cases of AxD are caused by heterozygous missense mutations within the coding region of the intermediate filament, glial fibrillary acidic protein (GFAP). However, little is known regarding the mechanisms by which GFAP dysfunction leads to disease phenotypes. Mouse models for the disease have begun to shed light on disease etiology. Utilizing mouse models and tissues from human patients, it was determined that inflammation occurs during AxD progression. However, the exact role of inflammation in promoting disease pathology is unknown. Given the lack of effective therapies in AxD, it will be important to determine if therapies that target the immune response have the potential to treat this devastating disease. The research proposed here will utilize mouse genetic models to investigate the role of monocytes and microglia in AxD pathology. We will determine the timing of monocyte and microglial accumulation in AxD and examine their phenotypes during disease initiation and progression. We will also determine if targeting a signaling axis involved in monocyte recruitment impacts disease phenotypes. These studies are expected to further our understanding of the role of inflammation in AxD and to determine if specific components of the inflammatory response should be investigated for treating AxD.
Alexander disease is a rare and generally fatal neurodegenerative disorder with no effective treatments. Although it has been documented that there is an immune response in the brains of Alexander disease patients, it is not known if this immune response contributes to disease symptoms or progression. We will study the role of a specific type of immune cell to determine if it plays a role in causing disease symptoms and if it could be a therapeutic target for treating the disease.
