Upregulating ANKHD1 in PS19 Mice Reduces Tau Phosphorylation and Mitigates Tau Toxicity-Induced Cognitive Deficits

Using the fly eye as a model system, we previously demonstrated that upregulation of the fly gene <i>mask</i> protects against FUS- and Tau-induced photoreceptor degeneration. Building upon this finding, we investigated whether the protective role of <i>mask</i> is conserved in mammals. To this end, we generated a transgenic mouse line carrying Cre-inducible <i>ANKHD1</i>, the human homolog of <i>mask.</i> Utilizing the TauP301S-PS19 mouse model for Tau-related dementia, we found that expressing ANKHD1 driven by CamK2a-Cre reduced hyperphosphorylated human Tau in 6-month-old mice. Additionally, ANKHD1 expression was associated with a trend toward reduced gliosis and preservation of the presynaptic marker Synaptophysin, suggesting a protective role of ANKHD1 against TauP301S-linked neuropathology. At 9 months of age, novel object recognition (NOR) testing revealed cognitive impairment in female, but not male, PS19 mice. Notably, co-expression of ANKHD1 restored cognitive performance in the affected female mice. Together, this study highlights the novel effect of ANKHD1 in counteracting the adverse effects induced by the mutant human Tau protein. This finding underscores ANKHD1's potential as a unique therapeutic target for tauopathies.