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

## TL;DR

Increasing ANKHD1 in mice reduces harmful Tau effects and improves cognitive function in female mice with Tau-related dementia.

## Contribution

ANKHD1 is shown to mitigate Tau toxicity and cognitive deficits in a mouse model of tauopathy.

## Key findings

- ANKHD1 expression reduced hyperphosphorylated human Tau in 6-month-old PS19 mice.
- ANKHD1 improved cognitive performance in female PS19 mice during novel object recognition testing.
- ANKHD1 was associated with reduced gliosis and preserved Synaptophysin levels in TauP301S mice.

## Abstract

Using the fly eye as a model system, we previously demonstrated that upregulation of the fly gene mask protects against FUS- and Tau-induced photoreceptor degeneration. Building upon this finding, we investigated whether the protective role of mask is conserved in mammals. To this end, we generated a transgenic mouse line carrying Cre-inducible ANKHD1, the human homolog of mask. 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.