TIA1 is required for microglial activation in tauopathy.

Abstract

The RNA-binding protein T cell intracellular antigen-1 (TIA1) regulates cellular stress responses and tau pathology, key contributors to the pathophysiology of tauopathies, including Alzheimer's disease (AD). TIA1 acts in peripheral monocytes to inhibit inflammation, but its function in central microglia, critical to neuroinflammation and disease progression, remains unknown. Here, we crossed TIA1 microglial conditional knockout (cKO) mice (using a Cx3cr1-driven Cre element) with the PS19 P301S MAPT mouse model of tauopathy and demonstrated that TIA1 promotes microglial activation, with a corresponding suppression of microglia activation upon TIA1cKO. We observe striking reductions in cytokine (Tnf-α and Il-1β) and sensome markers (Clec7a, Trem2, and Itgax); importantly, these reductions were accompanied by decreases in tau pathology. Proteomic analyses show TIA1 interaction with the microglial proteins C1Q, previously implicated in microglial activation. These results position TIA1 as a regulator of neuroinflammation and tauopathy in CX3CR1-expressing myeloid cells, including microglia, with potentially divergent functions in central versus peripheral immune compartments.