Sex Impact on Tau-Aggregation and Postsynaptic Protein Levels in the P301L Mouse Model of Tauopathy

Article type: Research Article

Authors: Buccarello, Lucia^{a; b; *} | Grignaschi, Giuliano^a | Castaldo, Anna Maria^{a; d} | Di Giancamillo, Alessia^b | Domeneghini, Cinzia^b | Melcangi, Roberto Cosimo^c | Borsello, Tiziana^{a; c}

Affiliations: [a] Department of Neuroscience, IRCCS-Mario Negri Institute for Pharmacological Research, Milan, Italy | [b] Department of Health, Animal Science and Food Safety, Universitá degli Studi di Milano, Italy | [c] Department of Pharmacological and Biomolecular Sciences, Universitá degli Studi di Milano, Italy | [d] Department of Biomedical Sciences for Health, Universitá degli Studi di Milano, Italy

Correspondence: [*] Correspondence to: Lucia Buccarello, PhD, Neuronal Death and Neuroprotection lab, Neuroscience Department, IRCCS-Istituto Di Ricerche Farmacologiche, “Mario Negri”, Via la Masa 19, 20156 Milano, Italy. Tel.: +39 02 39014475; E-mail: lucia.buccarello@marionegri.it.

Abstract: P301L transgenic (tg) mice well mimic features of human tauopathies and provide a good model for investigating the role of tau in neurodegenerative events. We here analyzed the possible interactions among phosphorylation of tau (p-tau), spine injury, neuronal death, and sex in the P301L mouse model of tauopathy. When compared to control mice (ctr), P301L transgenic mice (tg) presented a lower body weight, reduced survival rate, hyperphosphorylated tau, spine injury, and neuronal loss in both cerebral cortex and hippocampus at 15 months of age. Importantly, we found that pathological features were more pronounced in female than male tg mice. Recent reports underline 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 focused our attention on tau localization at dendritic spines. We detected high levels 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, such as GluN2A, GluN2B, GluA1, GluA2, Drebrin, and PSD-95, in P301L mice. 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 analyzed. The P301L-tg females showed a more severe synaptopathy compared to males. Future investigations on the postsynaptic role of p-tau will be necessary to understand its toxic effects and provide 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.

Keywords: Hyperphosphorylated tau, post-synaptic markers, sex, synaptopathy, tauopathy

DOI: 10.3233/JAD-161087

Journal: Journal of Alzheimer's Disease, vol. 56, no. 4, pp. 1279-1292, 2017