– Lysosome function in microglia and monocytes in AD pathogenesis: In funded studies with our collaborator (and my co-PI on the R01), Dr. Jin-Moo Lee from the department of Neurology at Washington University, we have observed that microglia demonstrate impaired phagocytosis and activation of TFE3, a master regulator of lysosomal biogenesis along with TFEB in myeloid cells. We are exploring the role of TFEB and TFE3 in microglia in AD mouse models using cell type specific targeting with genetic tools. In parallel studies, we have made the exciting observation that monocytes cross the blood brain barrier and are found adjacent to amyloid plaques with advanced amyloid pathology in mouse models. While these cells constitute only 5% of all microglia like cells next to plaques, stimulating their entry into the brain and stimulating lysosome biogenesis in these more readily targetable cell types (as compared with CNS resident microglia) could be an attractive strategy to stimulate amyloid plaque degradation to benefit AD pathogenesis.