Abstract: Microglia are the primary immune cells of the brain. These resident macrophages play critical roles not only in immunity, but also in brain development and homeostasis. In the adult brain, microglia constantly extend and retract their processes to survey the local environment and clear any pathological insults/injury. In the Alzheimer's disease (AD) brain, studies have identified activated microglia that surround amyloid-β plaques, one of the central and hallmark pathologies of the disease, and transcriptional profiling of these cells has identified a unique signature – termed disease-associated microglia (DAMs). However, it remains unclear whether this microglial response to plaques is beneficial or harmful to disease. To address this question, we have developed a novel inducible reporter mouse that allows for specific targeting of DAMs. This novel reporter mouse produces destabilized Cre (ddCre) at the Cst7, a gene that highly and specifically upregulated in DAMs, locus allowing us to effectively label or knockout Cst7 expression by the administration of trimethoprim (TMP). TMP is non-toxic and avoids the caveats associated with CreERT2 system-dependent tamoxifen. Here, we will use our Cst7ddCre line to evaluate the roles of TREM2, NLRP3, and CST7 in disease progression, and their distinct function at different ages/disease stages, as well as the fate of DAM's following Ab immunotherapy. We will assess behavior, cognition, glia, amyloid, tau, synapses, neurons, dystrophic neurites, NfL, as well as explore gene expression changes (via bulk tissue RNAseq) and spatial transcriptomics (via MERFISH) utilizing floxed Trem2, Nlrp3, or Cst7 KO mice crossed to 5xFAD or 5xFAD/hTau mice. These findings will elucidate the distinct functions of DAMs during disease and provide insights into new therapeutic approaches for AD.