Dihydrotestosterone Supplementation in P301S Female Mice Exacerbates Tauopathy and Microgliosis via the TR4-Trem2 axis

Alzheimer's disease (AD) disproportionately affects women, who exhibit greater vulnerability to Tau pathology and neuroinflammation. While estrogen and progesterone have been extensively studied in this context, the effects of androgens on female AD pathophysiology are largely unexplored. Here, we report that supplementation with the non-aromatizable androgen dihydrotestosterone (DHT) exacerbates Tau pathology in female tauopathy models, with microglia as a main driver of this effect. DHT treatment upregulates proinflammatory gene expression in microglia and promotes the disease-associated microglia (DAM) phenotype. Genetic deletion of Trem2 prevented DHT-driven neuroinflammation and Tau pathology exacerbation. Surprisingly, canonical androgen receptor (AR) signaling is dispensable for these DHT-induced effects in microglia. We identified an orphan nuclear receptor, TR4, as a mediator of DHT-driven effects through its transcriptional regulation of Trem2 in microglia. Moreover, TR4 protein levels are elevated in postmortem brain tissue from Braak stage 6 female AD patients and correlate with p-Tau levels. Together, our findings identify a non-canonical DHT–TR4–Trem2 signaling axis in microglia and position TR4 as a previously unrecognized regulator of neuroinflammation in female neurodegeneration, providing mechanistic insights into sex-specific vulnerabilities in AD. This GEO record is for the hippocampal bulk RNA sequencing data generated for our hormonal treatment paradigm.