More women than men have Alzheimer's disease (AD), suggesting that loss of estrogen may increase the risk for AD in postmenopausal women. Recent studies to demonstrate that estrogen protects Alzheimer's patients have had mixed results. In the January 22 advanced online publication in PNAS, Sozos Papasozomenos and Alikunju Shanavas at the University of Texas demonstrate that testosterone may prove beneficial in preventing the disease.

The researchers used an animal model to test the effects of testosterone and estradiol on heat shock induced phosphorylation of tau, the major component of the neurofibrillary tangles that are associated with AD. They found that testosterone, but not estradiol, could prevent phosphorylation of the microtubule-associated protein, specifically at Ser404.

Extracts from the forebrains of heat-shocked rats were tested for activity of glycogen synthase kinase-3β GSK-3β , cyclin-dependent kinase 5 (Cdk5), and c-Jun N-terminal kinase (JNK), which had previously been shown to be involved in tau phosphorylation. In the presence of testosterone, only GSK-3β activity was affected, being significantly reduced. Using phosphospecific antibodies, the authors showed the androgen to prevent phosphorylation of Tyr216, which is required for full activation of the kinase.

This work provides a molecular basis for previous observations that men with lower plasma testosterone are more susceptible to developing Alzheimer's.—Tom Fagan

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  1. This research group uses hyperthermia to induce a form of generalized stress that this group calls "heat shock" in its reports, but it is my understanding that this group is alone in application of this nomenclature. Exposure of cultured cells (not living animals) is a more accepted protocol for inducing "heat shock" and studying "heat shock proteins", many of which act as chaperones, as a means of defense against the protein denaturation caused by the elevated temperature. Exposure of living animals to a heated environment is most typically used to model the human febrile state (i.e., fever). Elevation of body temperature has a myriad of effects, both systemic and neurological. In general, metabolism is accelerated, at least within a limited range. At very supraphysiological levels, proteins unfold and denature, and cells die.

    This report exemplifies an important stage in the study of the molecular pathology of tau, i.e., moving into live animal models. Rodent tau is not identical to its human counterpart, and rodent tau is not competent to form neurofibrillary tangles. Transgenic mice bearing human tau with the mutation that causes familial frontotemporal dementia have recently been developed by Mike Hutton and his colleagues at Mayo Jacksonville. The neurons in the brains of these transgenic mice, when exposed to a well-documented insult such as amyloid peptides, are now competent to assume a conformation highly similar to neurofibrillary tangles (Lewis et al. 2001, Gotz et al. 2001). This rodent will now be a valuable tool for evaluating in vivo the role in tangle formation for various protein kinases and phosphatases as well as small molecules (e.g., glycosaminoglycans). In light of the rat "heat shock" data, it would be very interesting to expose a tangle-competent mouse to hyperthermia and assay to determine whether this insult modifies the intensity or time course of tangle formation.
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    References:

    . Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001 Aug 24;293(5534):1487-91. PubMed.

    . Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science. 2001 Aug 24;293(5534):1491-5. PubMed.

  2. The authors bring up some interesting points and I concur that sex steroid hormones probably play a role, whether directly or indirectly, in the pathogenesis of AD. However, the authors' conclusions fail to consider at least two confounding factors. One might suspect that there is a gender difference in the expression of sex steroid hormone receptors, yet the experiment was only performed on female rats. It would be interesting to see what would occur if gonadectomized male rats were administered estrogen. It might well be that one would see the same results of administering testosterone to gonadectomized female rats.
    In addition, the effect of alterations in gonadotropin secretion was not considered. Gonadotropins have been shown to upregulate CDK 5 in reproductive tissues (Musa FR 2000). Therefore, in vivo, any effects of the sex steroids might be partially mediated by alterations in gondadotropin secretion.

    One other issue that may be of importance is that the experiment was performed during the peri-pubertal period. Future experiments should probably be delayed until the rats have completed puberty. This is because sex steroid receptor expression might be developmentally regulated.

References

News Citations

  1. Neuroprotection from Testosterone? (And a Link Between Hysterectomy and Parkinson's)

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Further Reading

Papers

  1. . Androgens protect against apolipoprotein E4-induced cognitive deficits. J Neurosci. 2002 Jun 15;22(12):5204-9. PubMed.