Project Summary Alzheimer’s disease (AD) is an irreversible, progressive form of dementia and a leading cause of death globally. Genome-wide association studies have identified Triggering Receptor Expressed on Myeloid cells 2 (TREM2) variants that confer risk for AD. TREM2 is an integral membrane receptor exclusively expressed on myeloid cells that mediates immune responses. Expression of TREM2 varies within each CNS region and disease state, with high expression in white matter. Using a humanized tau (hTau) mouse model, our lab has identified the input of CD45hi peripheral cells that are recruited predominantly to white matter regions and generally excluded from gray matter regions. Coincident with infiltration of these CD45hi cells, TREM2 expression is increased in white matter, cerebellum, and brainstem, largely at 12 months of age, suggesting a connection between TREM2 and peripheral immune response during later stage tau pathology. Intriguingly, blocking entry of these cells into the brain parenchyma by abrogating CCR2-mediated extravasation exacerbates tau pathology within the white matter and promotes axonal damage, but CD45hi cells continue to accumulate in the choroid plexus indicating other signaling pathways participating in their recruitment. Similarly, in the absence of TREM2 the number of CD45hi cells decreased, the CD45hi cells no longer remained localized to white matter regions, and tau pathology was worsened. Therefore, we posit that TREM2 modulates white matter pathology in a mouse model of tauopathy via peripheral immune cell recruitment. We will examine this hypothesis in the following aims: 1) identify phenotype, location, and associated pathology of these immune populations in hTau and hTau;Trem2-/- mice; 2) dissect the TREM2-mediated mechanism of extravasation of these immune cells into the brain using slice cultures and unbiased spatial transcriptomics; 3) modulate TREM2 input in a disease-progression dependent manner using conditional microglial TREM2 knockout mice to determine the functional behavior outputs and correlate them to regions of white matter pathology as a consequence of these immune cells. The knowledge gained from these studies will be important to understanding the interface between innate and peripheral immunity modulated by TREM2 in the context of both early and late stage tau pathology and will be invaluable for the development of novel therapeutic approaches in timing and modification of peripheral immune responses, not only for AD, but neurodegeneration more generally.