Dose and temporal pattern of estrogen exposure determines neuroprotective outcome in hippocampal neurons: Therapeutic implications

To address controversies of estrogen therapy, in vitro models of perimenopause and prevention vs. treatment modes of 17β-estradiol (E ₂) exposure were developed and used to assess the neuroprotective efficacy of E₂ against β-amyloid-1-42 (Aβ_1-42)- induced neurodegeneration in rat primary hippocampal neurons. Low E₂ (10 ng/ml) exposure exerted neuroprotection in each of the perimenopausal temporal patterns, acute, continuous, and intermittent. In contrast, high E ₂ (200 ng/ml) was ineffective at inducing neuroprotection regardless of temporal pattern of exposure. Although high E₂ alone was not toxic, neurons treated with high-dose E₂ resulted in greater Aβ_1-42-induced neurodegeneration. In prevention vs. treatment simulations, E₂ was most effective when present before and during Aβ_1-42 insult. In contrast, E₂ treatment after Aβ_1-42 exposure was ineffective in reversing Aβ-induced degeneration, and exacerbated Aβ_1-42-induced cell death when administered after Aβ_1-42 insult. We sought to determine the mechanism by which high E₂ exacerbated Aβ_1-42-induced neurodegeneration by investigating the impact of low vs. high E₂ on Aβ_1-42-induced dysregulation of calcium homeostasis. Results of these analyses indicated that low E₂ significantly prevented Aβ_1-42-induced rise in intracellular calcium, whereas high E₂ significantly increased intracellular calcium and did not prevent Aβ_1-42-induced calcium dysregulation. Therapeutic benefit resulted only from low-dose E₂ exposure before, but not after, Aβ_1-42-induced neurodegeneration. These data are relevant to impact of perimenopausal E₂ exposure on protection against neurodegenerative insults and the use of estrogen therapy to prevent vs. treat Alzheimer's disease. Furthermore, these data are consistent with a healthy cell bias of estrogen benefit.