Puerarin suppression of Aβ_1-42-induced primary cortical neuron death is largely dependent on ERβ

Recent study has suggested that estrogen replacement therapy (ERT) can decrease the risk of the development of Alzheimer's disease (AD), and phytoestrogen has been proposed as a potential alternative to ERT. In this study, we investigated the protective function of puerarin (a phytoestrogen isolated from puerarin lobate) against amyloid beta (Aβ_1-42)-induced toxicity in cortical neurons and established the connection between such a protection and estrogen receptor (ER) activation. Puerarin suppressed Aβ_1-42-induced cortical neuron death in a concentration-dependent manner. Morphological examination showed that puerarin not only suppressed Aβ_1-42-induced decrease in neuron numbers, but also promoted neurite growth. In addition, we found that the neuroprotection of puerarin was dependent on the activation of estrogen receptors (ERs), as demonstrated by activation of ERE-reporter gene. Puerarin preferentially up-regulated the expression of ERβ but not ERα, and ERβ-specific siRNA significantly reduced the neuroprotection of puerarin. Taken together, our results indicated that puerarin is neuroprotective against Aβ_1-42 toxicity via the activation of estrogen receptors, and ERβ plays a key role in the process. Our novel findings provide a potential strategy for the prevention of neurodegeneration and the treatment of AD.