Sexual Dimorphic Accumulation of Hyperphosphorylated Tau in Tauopathies: The Possible Role of Estrogen Receptor α

Background: We found in cognitively intact elderly subjects that women have more and faster hyperphosphorylated Tau (p-Tau) accumulation than men in the entorhinal cortex (EC) during aging. We investigated whether similar sex differences occur in tauopathies without or with very little β-amyloid (Aβ) deposition and whether they are associated with local estrogen receptor α (ERα).<br><br>Methods: The EC level of p-Tau, ERα, early growth response factor 1 (EGR1) and acetylcholinesterase (AChE) was determined in primary age-related tauopathy (PART) donors (Braak I-IV), PS19 mice of 3 and 7 months, and - following 17β-estradiol (E2) administration - in SH-SY5Y cells with or without p-Tau overexpression.<br><br>Results: PART females exhibited a faster and stronger p-Tau accumulation in relation to Braak staging than males, accompanied by sex-dependent changes in ERα and AChE. A different but also sex-dependent onset and development of p-Tau accumulation was found in PS19 mice. Overexpression of p-Tau in SH-SY5Y cells led to increased levels of total Tau (t-Tau), ERα, and EGR1. &nbsp;E2 treatment reduced ERα and p-Tau expression in SH-SY5Y cells with or without p-Tau–overexpression. E2 also reduced EGR1 and AChE expression in cells with p-Tau overexpression.<br><br>Interpretation: P-Tau accumulation in the absence of Aβ in the EC shows clear sex differences in tauopathies such as PART and PS19 mice. Increased ERα may exacerbate p-Tau accumulation, while local levels of E2 and ERα change in opposite directions.