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The Journal of Neuroscience, June 9, 2004, 24(23):5315-5321; doi:10.1523/JNEUROSCI.0913-04.2004

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Neurobiology of Disease
Estrogen and Androgen Protection of Human Neurons against Intracellular Amyloid _1-42 Toxicity through Heat Shock Protein 70

Yan Zhang,^1,4 Nathalie Champagne,⁴ Lenore K. Beitel,⁴ Cynthia G. Goodyer,² Mark Trifiro,^3,4 and Andréa LeBlanc^1,4

Departments of ¹Neurology and Neurosurgery, ²Pediatrics, and ³Human Genetics, McGill University, Montréal QB H3A 1B1, Canada, and ⁴The Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal QB H3T 1E2, Canada

Intracellular amyloid peptide (iA_1-42) 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 iA_1-42 toxicity, because both these hormones have a wide range of neuroprotective actions. At physiological concentrations, 17--estradiol, testosterone, and methyl testosterone reduce iA_1-42-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 iA_1-42 blocks the toxicity of iA_1-42. We conclude that estrogen and androgens protect human neurons against iA_1-42 toxicity by increasing the levels of Hsp70 in the neurons.

Key words: intracellular amyloid; estrogen; androgen; neuroprotection; human neurons; Hsp70

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Received March 12, 2004; revised April 21, 2004; accepted April 22, 2004.

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