Gender-genotype interaction lead to an increase of cognitive impairment, locomotor dysfunctions and neurola damage in young and aged female TAU P301L mice model of tauopathy

P301L transgenic (TG) mice well mimic features of human tauopathies and provide a good model for investigating Tau role in neurodegenerative events. We analysed the possible interaction among P-Tau, spine injury, neuronal death and sex differences in P301L transgenic mice at 15 months of age. Comparing CTR versus P301L transgenic mice, TG mice present a lower body weight, a less survival rate, hyperphosphorylated Tau, spine injury and neuronal loss in both cerebral cortex and hippocampus at the time point analysed. Importantly, pathological features described are more pronounced in female than male TG mice. Recent reports underlined that Tau may be localized within both pre- and post-synaptic compartments, suggesting that it may possibly induce or contribute to synaptic dysfunction. Therefore, we focus our attention on Tau localization at the dendritic spine level. We detected a huge level of both Tau and P-Tau in dendritic spine of P301L transgenic mice. In addition, P-Tau correlated with a significant reduction of post-synaptic markers: NR2a, NR2b, Glur1, Glur2, Debrin and PSD-95 levels in P301L Tg. The P-Tau levels are higher in female than in male mice, and the increased P-Tau was consistent with a proportional decrease in the post-synaptic marker levels analysed. The P301L tg females presented a more severe synaptopathy compared to males. Future investigations on P-Tau postsynaptic role will be necessary for understanding its toxic effects and providing insights into new therapeutic targets for maintaining spine integrity, highlighting the importance of Tau toxicity as well as the impact of sex on tau-pathology.