**Meng-Chao Tsai 1,**†**, Shyh-Hsiang Lin 2,3,4,**†**, Kiswatul Hidayah <sup>2</sup> and Ching-I Lin 5,\***


Received: 2 August 2019; Accepted: 23 September 2019; Published: 3 October 2019

**Abstract:** β-amyloid formation in the brain is one of the characteristics of Alzheimer's disease. Exposure to this peptide may result in reentry into the cell cycle leading to cell death. The phytoestrogen equol has similar biological effects as estrogen without the side effects. This study investigated the possible mechanism of the neuron cell-protecting effect of equol during treatment with Aβ. SH-SY5Y neuroblastoma cells were treated with either 1 μM S-equol or 10 nM 17β-estradiol for 24 h prior to 1 μM Aβ (25–35) exposure. After 24 h exposure to Aβ (25–35), a significant reduction in cell survival and a reentry into the cell cycle process accompanied by increased levels of cyclin D1 were observed. The expressions of estrogen receptor alpha (ERα) and its coactivator, steroid receptor coactivator-1 (SRC-1), were also significantly downregulated by Aβ (25–35) in parallel with activated extracellular signal-regulated kinase (ERK)1/2. However, pretreatment of cells with S-equol or 17β-estradiol reversed these effects. Treatment with the ER antagonist, ICI-182,780 (1 μM), completely blocked the effects of S-equol and 17β-estradiol on cell viability, ERα, and ERK1/2 after Aβ (25–35) exposure. These data suggest that S-equol possesses a neuroprotective potential as it effectively antagonizes Aβ (25–35)-induced cell cytotoxicity and prevents cell cycle reentry in SH-SY5Y cells. The mechanism underlying S-equol neuroprotection might involve ERα-mediated pathways.

**Keywords:** S-equol; 17β-estradiol; estrogen receptor alpha; cell cycle; β-Amyloid; Alzheimer's disease
