Estrogen and androgen protection of human neurons against intracellular amyloid β1-42 toxicity through heat shock protein 70

Abstract

Intracellular amyloid β peptide (iAβ1-42) accumulates in the Alzheimer's disease brain before plaque and tangle formation (Gouras et al., 2000) and is extremely toxic to human neurons (Zhang et al., 2002). Here, we investigated whether androgen and estrogen could prevent iAβ 1-42 toxicity, because both these hormones have a wide range of neuroprotective actions. At physiological concentrations, 17-β-estradiol, testosterone, and methyl testosterone reduce iAβ1-42-induced cell death by 50% in neurons treated after the injection and by 80-90% in neurons treated 1 hr before the injection. The neuroprotective action of the hormones is mediated by receptors, because the estrogen receptor (ER) antagonist tamoxifen and the androgen receptor (AR) antagonist flutamide completely block the estrogen- and androgen-mediated neuroprotection, respectively. Transcriptional activity is required for the neuroprotective action, because dominant negative forms of the receptors that block the transcriptional activity of the ER and AR prevent estrogen- and androgen-mediated neuroprotection. Proteomics followed by Western blot analyses identified increased levels of heat shock protein 70 (Hsp70) in testosterone- and estrogen-treated human neurons. Comicroinjection of Hsp70 with the iAβ1-42 blocks the toxicity of iAβ1-42. We conclude that estrogen and androgens protect human neurons against iAβ 1-42 toxicity by increasing the levels of Hsp70 in the neurons.