Estrogens Inhibit Amyloid-β-Mediated Paired Helical Filament-Like Conformation of Tau Through Antioxidant Activity and miRNA 218 Regulation in hTau Mice

Article type: Research Article

Authors: Guglielmotto, Michela^{a; b} | Manassero, Giusi^{a; b} | Vasciaveo, Valeria^{a; b} | Venezia, Marika^{a; b} | Tabaton, Massimo^c | Tamagno, Elena^{a; b; *}

Affiliations: [a] Department of Neuroscience, University of Torino, Torino, Italy | [b] Neuroscience Institute of Cavalieri Ottolenghi Foundation (NICO), University of Torino, Orbassano, Torino, Italy | [c] Unit of Geriatric Medicine, Department of Internal Medicine and Medical Specialties (DIMI), University of Genova, Genova, Italy

Correspondence: [*] Correspondence to: Elena Tamagno PhD, Neuroscience Institute Cavalieri Ottolenghi, University of Torino, Regione Gonzole 10, 10043 Orbassano, Torino, Italy. Tel.: +39 0116707764; E-mail: elena.tamagno@unito.it.

Abstract: Background:The risk of developing Alzheimer’s disease as well as its progression and severity are known to be different in men and women, and cognitive decline is greater in women than in men at the same stage of disease and could be correlated at least in part on estradiol levels. Objective:In our work we found that biological sex influences the effect of amyloid-β42 (Aβ42) monomers on pathological tau conformational change. Methods:In this study we used transgenic mice expressing the wild-type human tau (hTau) which were subjected to intraventricular (ICV) injections of Aβ peptides in nanomolar concentration. Results:We found that Aβ42 produces pathological conformational changes and hyperphosphorylation of tau protein in male or ovariectomized female mice but not in control females. The treatment of ovariectomized females with estradiol replacement protects against the pathological conformation of tau and seems to be mediated by antioxidant activity as well as the ability to modulate the expression of miRNA 218 linked to tau phosphorylation. Conclusion:Our study indicates that factors as age, reproductive stage, hormone levels, and the interplay with other risk factors should be considered in women, in order to identify the best appropriate therapeutic approach in prevention of cognitive impairment.

Keywords: Alzheimer’s disease, antioxidants, estradiol, miRNA, tau protein

DOI: 10.3233/JAD-200707

Journal: Journal of Alzheimer's Disease, vol. 77, no. 3, pp. 1339-1351, 2020