Abstract BACE1 is an enzyme required for Aβ generation, and chemical inhibition of BACE1 has been explored for reducing Aβ generation. Five brain-penetrable BACE1 inhibitory dugs were recently tested in human trials. Unfortunately, despite a noted reduction in Aβ plaque loads, these clinical trials were terminated, largely due to neuronal and synaptic toxicity. This setback indicates the importance to known more BACE1 biology and to develop safer BACE1 inhibitors for AD treatment, especially considering the growing evidence from anti- Aβ trials that reducing Aβ plaques early can lead to reduction of other AD pathologies. In this proposal, we aim to test a novel hypothesis that increasing inhibition of BACE1 in glial cells, along with boosting microglial phagocytic functions, will reduce AD pathologies while minimizing synaptic side effects. This hypothesis is supported by our recent observations that Bace1 deletion in microglia facilitates the transition of homeostatic microglia to more phagocytic stage-1 disease-associated microglia (DAM-1). Consistently, deletion of microglial Bace1 in 5xFAD mice reduces amyloid deposition. If Bace1 in astrocytes is deleted, the expression of genes, such as clusterin (Clu), CXCL14 and ApoE, important for removal of amyloid plaques by astrocytes, is increased. These results suggest that BACE1 inhibition in glial cells has a beneficial effect on the clearance of amyloid plaques. However, many questions remain to be answered. For example, it is not clear whether Bace1 deletion will affect tau pathology. We do not yet know how BACE1 inhibition will enhance microglia to remove tau pathology. Considering the known role of chemoattractant molecule CXCL14 in mediating migration of immune cells and reduced levels of CXCL14 in AD brains, we will ask whether the expected elevated levels of CXCL14, in response to the inhibition by BACE1, will promote phagocytic function of microglia. This question will be address by utilizing an inducible transgenic mouse model that has already been generated. In this proposal, we will explore whether deletion of BACE1 in PS19 mouse microglia will reduce tau pathology in Aim 1. In Aim 2, we will ask whether a low dose inhibition of BACE1 in AD triple-transgenic model coupled with deletion of Bace1 in microglia will reduce both amyloid and tau pathologies effectively. In Aim 3, we will investigate whether enhancing expression of CXCL14 will promote microglia migration and phagocytosis. These studies are centered on improving microglia function and the knowledge gained from this study will help to develop a therapeutic approach that will favor BACE1 inhibition in glial cells coupled with molecular boosters of microglia phagocytic function for AD treatment.