Investigating the role of EFhd2 protein in modulating tau pathology in a tauopathy mouse model.

Accumulation of abnormally aggregated tau is the main pathological hallmark in tauopathies, including Alzheimer's disease (AD). Increasing evidence suggests that pretangle oligomeric tau aggregates exert neurotoxicity, while neurofibrillary tangles (NFTs) may represent less toxic structures that possibly delay cellular demise. A multitude of in vitro studies have endorsed the low propensity of tau protein to aggregate without an external aggregation inducer. Hence, studying tau-interacting proteins has garnered research attention in the last decade as potential contributors to pathological tau aggregation. We identified EF-Hand Domain Family Member D2 (EFhd2) protein as a tau-associated protein in JNPL3 mouse model and postmortem tauopathies tissues. Recently, we have shown that EFhd2 interacts with tau filaments in vitro, promoting the formation of large unique aggregated structures. Based on these findings and others, we hypothesized that EFhd2 might contribute to the formation of tau aggregates in vivo. To test this hypothesis, we examined the impact of deleting the Efhd2 gene on the progressive pathological phenotype and neuropathological changes in Tau P301L -expressing mice. The results indicated only modest, sex-specific differences in lifespan associated with Efhd2 deletion in Tau P301L mice. Independent of p-values, Efhd2 deletion also showed a medium-to-large main effect in reducing cortical pSer422 and PHF1 tau levels in aged mice, consistent with attenuated late-stage tau aggregation. Moreover, Efhd2 deletion showed effect-size-based trends toward higher Alz50 staining, suggesting an increase in early pathological tau conformations. These findings indicate that Efhd2 deletion is associated with a shift in tau species toward earlier conformational states alongside reduced markers of later-stage aggregation. The observed modest effects do not establish a direct mechanistic role for EFhd2 in tau aggregation in vivo. Rather, they suggest that EFhd2 may function as a modulatory component within a broader protein network influencing tau pathology. Future studies will determine to the extent to which these effects arise from direct modulation of tau aggregation, altered cellular pathways, or interactions within the EFhd2-associated protein network.