Zhang Y, Champagne N, Beitel LK, Goodyer CG, Trifiro M, LeBlanc A.
Estrogen and androgen protection of human neurons against intracellular amyloid beta1-42 toxicity through heat shock protein 70.
J Neurosci. 2004 Jun 9;24(23):5315-21.
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Multiple lines of evidence have suggested that estrogen (and possibly androgens) protect against AD, although the mechanism(s) are unclear. Zhang et al. have used a well-defined model to look specifically at the effect of these steroid hormones on the neurotoxicity of intracellular Aβ1-42. These researchers have used microinjection of Aβ into primary human neurons to directly demonstrate intracellular Aβ neurotoxicity. Exposure of neurons to physiological levels of estrogen or testosterone preceding microinjection was found to significantly protect neurons from the microinjected Aβ.
In an elegant series of experiments, these researchers demonstrated that this protection occurred via transcriptional activation of the respective hormone receptors. This finding is important because it rules out the possibility that the neuroprotection by these hormones results from their non-specific antioxidant activity. One protein shown to be upregulated by hormone treatment is HSP70, which has previously been found to protect against other neurotoxic aggregating proteins (e.g., polyglutamine repeat-containing proteins). Coinjection of purified HSP70 protein with Aβ was shown to be protective in these neurons, supporting hormone-induced HSP70 upregulation as a component of the molecular mechanism of neuroprotection.
As admitted by the authors of this paper, the HSP70 co-injection experiments do not prove HSP70 upregulation is the critical protective mechanism; clearly other hormone-induced changes in neuronal physiology may be involved. The coinjection experiments could also be misleading, as it is unclear if they result in physiological levels of HSP70; it is also possible that relevant HSP70/Aβ interactions occurred in the microsyringe before injection.
Nevertheless, this is an important paper because it demonstrates that estrogen and androgen neuroprotection against Aβ toxicity can occur independent of any effects these hormones might have on Aβ production itself. The effect of estrogen on Aβ and β amyloid accumulation have been somewhat controversial, and recently Heikkinen et al (2004) have reported that estrogen treatment had no effect on Aβ accumulation in a double transgenic (APP + PS1) mouse model, although they did observe a positive effect on spatial learning. If intraneuronal Aβ plays a role in mental dysfunction, estrogen treatments may be protective, even if they do not affect extracellular Aβ levels.
Heikkinen T, Kalesnykas G, Rissanen A, Tapiola T, Iivonen S, Wang J, Chaudhuri J, Tanila H, Miettinen R, Puoliväli J.
Estrogen treatment improves spatial learning in APP + PS1 mice but does not affect beta amyloid accumulation and plaque formation.
Exp Neurol. 2004 May;187(1):105-17.