Progestogens reduce tau phosphorylation via ERK 1/2 in a tau overexpression cell model

Several studies have suggested the neuroprotective effects of progestogens in neurodegenerative diseases. Among the most common neurodegenerative diseases are tauopathies. Tauopathies are characterized by the formation of neurofibrillary tangles within neurons, resulting from the aggregation of hyperphosphorylated tau protein, cytoskeleton impairment and, ultimately, cell death. However, the effect of progestogens on those processes needs to be further explored. Thus, this work aims to investigate the effect of progesterone and allopregnanolone on tau hyperphosphorylation in a cellular model of tau overexpression. We used a neuronal cellular model overexpressing the human tau protein (isoform 0N4R) fused with EGFP. The data showed that progesterone effectively decreased the accumulation of overexpressed EGFP-tau. In addition, both compounds reduced tau phosphorylation in different sites, as progesterone reduced at the AT8 and allopregnanolone at AT180 site. The attenuation of its phosphorylation appears to be related to inhibiting the kinase activity of enzymes involved in tau phosphorylation, such as ERK 1/2. Thus, the progestogens tested showed promising neuroprotective potential for the treatment of tauopathies, especially by attenuating hyperphosphorylated forms that give rise to paired helical filaments and neurofibrillary tangles, probably due to modulation of intracellular pathways.