29 October 2001. Estrogen replacement therapy may protect postmenopausal women from Alzheimer's disease, according to some epidemiological studies. For example, a recent short trial of high-dose 17β-estradiol found significant improvement in cognitive test performance in postmenopausal women with AD (Asthana et al., 2001). While the role of estrogen in AD is being debated, cell biologists are looking for mechanisms by which the hormone might prevent neurodegeneration. Candidate mechanisms include transcriptional and post-transcriptional processes, as well as the hypothesis that estrogen helps prevent programmed cell death. In the October 15 Journal of Neuroscience, Andrea LeBlanc and colleagues at McGill University in Montreal report that this protection could be mediated by the inhibition of caspase-6.

Spurred by disparate bits of evidence that caspase-6 may play a role in the pathogenesis of AD, LeBlanc's group assessed the effects of several neuroprotective agents against caspase-6-mediated apoptosis. They found that 17β-estradiol prevents caspase-6-mediated neuronal death in vitro, whereas neither the transcriptionally inactive 17α-estradiol nor testosterone do so. The authors suggest that this is mediated by a caspase-inhibitory factor (CIF) via the estrogen receptor. Because 17β-estradiol induces CIF activity within minutes, this pathway apparently does not require new protein synthesis. Junying Yuan, of Harvard Medical School, is cautious in appraising these results. "There is no evidence that the CIF in this paper is actually one activity, which may or may not be relevant to the effect of the hormone on AD," she says.—Hakon Heimer

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Papers

  1. . High-dose estradiol improves cognition for women with AD: results of a randomized study. Neurology. 2001 Aug 28;57(4):605-12. PubMed.

Primary Papers

  1. . 17-beta-estradiol induces an inhibitor of active caspases. J Neurosci. 2001 Oct 15;21(20):RC176. PubMed.