Introduction　Microglial　dysfunction　is　characteristic　of　Alzheimer＇s　disease　(AD),　with　triggering　receptor　expressed　on　myeloid　cells　2　(TREM2)　and　transcription　factor　PU.1　playing　crucial　roles.　However,　the　relationship　between　TREM2　and　PU.1　remains　unclear.Methods　We　investigated　TREM2　and　PU.1　expression　patterns　in　the　5xFAD　mouse　AD　model.　Experimental　approaches　included　quantitative　PCR,　western　blotting,　immunofluorescence　staining,　chromatin　immunoprecipitation,　and　luciferase　reporter　assays　to　examine　the　interaction　between　PU.1　and　TREM2.　The　phagocytic　function　of　microglial　cells　was　evaluated　using　A　beta　42　and　Nile　red　fluorescent　microsphere　phagocytosis　assays.Results　TREM2　and　PU.1　expression　significantly　correlated　with　brain　beta-amyloid　(beta)　deposition.　PU.1　directly　interacted　with　the　TREM2　promoter　region,　promoting　its　transcription　and　potently　impacting　microglial　phagocytosis.　PU.1　overexpression　amplified　TREM2　expression,　while　PU.1　knockdown　reduced　it.Discussion　Our　findings　reveal　a　novel　regulatory　mechanism　where　PU.1　directly　modulates　TREM2　transcription　in　activated　microglia　during　AD　progression.　These　insights　highlight　the　potential　of　TREM2　and　PU.1　as　therapeutic　targets　in　AD　treatment.