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Center for Reproductive Sciences Columbia University Medical Center New York, New York 10032
Address all correspondence and requests for reprints to: Dr. Neil J. MacLusky, Center for Reproductive Sciences, Columbia University Medical Center, 630 West 168th Street, New York, New York 10032. E-mail: nm274{at}columbia.edu.
The contribution of estrogens to the prevention of neurodegenerative disorders has attracted considerable attention over the last few years as a result of conflicting data from clinical trials, some of which have shown protective effects of postmenopausal estrogen-based hormone replacement therapy (HRT), whereas others (including the recently concluded Women’s Health Initiative trial) have revealed no significant benefit. Although the reason for these apparently discrepant results remains the subject of heated debate, a growing body of evidence suggests that individual women may exhibit variable neuroprotective responses to HRT, in part because of interactions with other known risk factors for neurodegenerative disease. One such risk factor, which modulates the effects of HRT on rates of cognitive decline in aging women, is the expression pattern of allelic variants of apolipoprotein E (apoE). The paper by Nathan et al. (1) in this issue of Endocrinology indicates why this may be the case. Trophic effects of the natural ovarian estrogen, estradiol-17ß, on neurite growth in cultured mouse cerebral cortical neurons are reported to be critically dependent on apoE expression. Moreover, responses to estradiol-17ß are shown to be dependent on the type of apoE present: whereas estradiol-17ß is neurotrophic in the presence of human apoE 
2 or apoE 3, the apoE 4 variant, which has been associated with the progression of late onset Alzheimer’s disease, does not support this response.
The concept that HRT might have beneficial effects on the aging brain evolved initially from studies in laboratory animals. Almost 3 decades ago, estradiol-17ß was shown to exert neurotrophic effects in tissue explants derived from the developing mouse hypothalamus and preoptic area (2). Synaptogenic effects of estradiol-17ß were later demonstrated to occur in the adult brain, including regions of the brain, such as the hippocampus, that are important for cognitive function (3, 4). In various models of neuronal damage, natural and synthetic estrogens were reported to enhance cell survival (5), whereas estradiol-17ß treatment was shown to enhance nonamyloidogenic processing of the Alzheimer amyloid precursor protein (6). Estradiol-17ß was also found to have positive effects on maintenance of the neurotransmitter systems that undergo degeneration in Alzheimer’s disease (7) and Parkinson’s disease (8). Taken together, these observations provided strong mechanistic support for the concept that postmenopausal HRT might slow or prevent neurodegenerative processes.
Clinical trials have, in general, provided only mixed support for this hypothesis while simultaneously highlighting the potential health risks of long-term postmenopausal HRT use (1, 9, 10, 11). Part of the problem appears to be that in human beings, unlike laboratory animals, effects of HRT may be confounded by a variety of other factors, which modulate or oppose the actions of the hormones. One particularly important genetic factor appears to be the expression pattern of apoE. Expression of different apoE alleles had previously been demonstrated to affect the risk of atherosclerosis (12) as well as the rate of progression of several human neurodegenerative diseases (13, 14), including Alzheimer’s dementia (15). Intriguingly, patterns of apoE expression were also found to significantly influence responses to HRT (16).
The mechanism underlying this interaction remained uncertain. One possibility was that it might reflect the known effects of apoE expression on atherosclerotic processes (12), with cerebral vascular compromise secondarily affecting the rate of cognitive decline (16). An alternative hypothesis, however, was suggested by studies aimed at elucidating the effects of estradiol-17ß on apoE expression in nerve cells. Studies in mice demonstrated that expression of apoE in different brain regions varied with stage of the female reproductive cycle (17), consistent with the hypothesis that estradiol-17ß might induce apoE expression in the brain, as had already been demonstrated for apoE in blood (18). Addition of apoE 3 was found to produce effects like those of estradiol-17ß on cultured neurons (19). Moreover, neuroprotective effects of estradiol-17ß were abolished in transgenic mice homozygous for deletion of the apoE gene (20). These observations raised the possibility that apoE might represent an integral component of the mechanisms mediating trophic responses of neurons to estrogen exposure.
The study by Nathan et al. (1) demonstrate that this is indeed the case. The growth-promoting effects of estradiol-17ß not only depend on the expression of apoE, they are also highly dependent on the nature of the apoE subtype. In cultured cells from the adult mouse cerebral cortex, estradiol-17ß increased both apoE levels and neurite outgrowth. The hormone had no effect on neurite outgrowth from mice lacking the apoE gene, or when only apoE 4 was exogenously supplied. ApoE 2, an apoE variant that has been associated with reduced risk of Alzheimer’s disease and increased age of onset, increased neurite length more than apoE 3 in the presence of estradiol-17ß. Cultures from mice transgenic for human apoE 3 were capable of responding to estradiol-17ß, whereas those from mice expressing only apoE 4 were relatively insensitive. Similarly, apoE 3 was accumulated in neurons to a greater extent than apoE 4 and was more effective in facilitating neuronal uptake of fatty acid. These data are consistent with the hypothesis that apoE may play an integral role in supporting the neurotrophic effects of estradiol-17ß and that patterns of apoE expression may have a profound impact on the sensitivity of the brain to estrogen action.
These observations have important implications for future studies on the effects of HRT. If expression of specific apoE alleles is required for estrogen to exert neurotrophic and neuroprotective effects, the pattern of apoE allele expression is likely to be important in determining the effectiveness of estrogen-based HRT. Synergism between apoE subtype expression and the effects of HRT has already been demonstrated with respect to the progression of atherosclerosis in postmenopausal women, for which estrogen use appears to be particularly beneficial in patients with no apoE 4 allele (12). The same situation may well be true for effects on neurodegenerative processes. Yaffe et al. (16) administered cognitive function tests over a number of years to women who were either taking estrogen-based HRT, had taken HRT at some time in the past, or who had never used HRT. In the women who did not express the apoE 4 variant, postmenopausal estrogen use reduced the risk of age-related cognitive impairment by almost 50%, compared with the women who never used estrogen. By contrast, apoE 4-positive women did not show a significant estrogen response (16). These data are consistent with the hypothesis that analysis of apoE variant expression may be predictive of whether HRT is likely to have long-term beneficial cognitive effects.
Much remains to be done. One of the key questions that remains to be answered is the extent to which the data presented by Nathan et al. (1) can be extrapolated to the normal brain. The work of Nathan et al. used cultures of dispersed neuronal and glial cells from the adult mouse cerebral cortex. It will be important in future to determine whether the effects of estrogens on the aging brain involve comparable apoE-dependent mechanisms. Published evidence is consistent with the view that effects of estradiol-17ß on the recovery of the mature brain from injury require apoE. Thus, in mice, enhancement of synaptic sprouting by estradiol-17ß in response to an entorhinal cortex lesions is dependent on apoE expression (21). However, neuronal damage, perhaps including the cellular damage inevitably incurred during the preparation of primary cell cultures, may result in reexpression of estrogen receptor mechanisms that are normally expressed only in development (22). Hence, it remains to be established whether these findings can be extrapolated to the regulation of neuronal growth and survival in the uninjured brain. As postulated by Nathan et al. (1), in dementia or after trauma, degeneration and repair may be in dynamic balance, with cognitive decline occurring when degenerative processes predominate. However, significant trophic responses to estradiol-17ß are also observed under conditions in which neurodegeneration is probably minimal (3, 4). These responses may contribute to the effects of estrogens on cognitive performance (23). It remains to be determined whether apoE is involved in the trophic actions of estradiol-17ß under normal physiological, as opposed to pathological, conditions.
A second question is how apoE is regulated by steroids other than estradiol-17ß. A wide range of estrogens and progestins have been used for HRT in postmenopausal women (10, 11). It remains to be determined how these different steroids affect apoE expression. The question of the specificity of the apoE response is critical because of the possibility that some combinations of hormonal agents could abrogate the beneficial effects of natural estrogens. For example, Nilsen and Brinton (24) have reported that whereas progesterone and 19-norprogesterone both potentiate the neuroprotective effects of estradiol-17ß, the opposite effect is observed with medroxyprogesterone acetate, the synthetic progestin used in the Women’s Health Initiative trial. Whether or not apoE expression is affected by other steroids is also important because of the fact that estradiol-17ß is not the only hormonal steroid with neuroprotective and neurotrophic properties. Recent work suggests that androgens may confer protection against neurodegenerative processes. Men with higher free testosterone levels appear to have a lower risk of developing Alzheimer’s disease (25), whereas reduced levels of the principal adrenal androgen, dehydroepiandrosterone, have been reported in Alzheimer’s disease patients (26). In laboratory studies, androgens and progestins have been reported to elicit neurotrophic and neuroprotective effects under a variety of experimental conditions (24, 27, 28). Although in some cases these effects may involve either interactions with estrogen or intermediate estrogen biosynthesis, in others they clearly do not (27). An intriguing hypothesis for future study is that apoE expression may represent a common link in steroid-activated neurotrophic responses. If so, effects of androgens, like those of estrogens, may be influenced by apoE genotype. Interestingly, this possibility has already been raised by preliminary clinical studies, which demonstrated interactions between testosterone and apoE 4 expression in men with Alzheimer’s disease, as well as an association between apoE 4 and circulating testosterone levels in men without the disease (29). These observations raise the possibility that the relationship between apoE expression and gonadal steroids may be multifactorial, with the apoE 4 allele directly affecting the risk of neurodegenerative disease via effects on neuronal growth and survival, as well as indirectly via reductions in testicular androgen secretion.
Perhaps the most intriguing aspect of the observations of Nathan et al. (1), however, is the potential for development of novel strategies for replacement therapy designed to directly target the regulation of neural apoE expression. The adverse effects of conventional HRT are primarily associated with responses that do not involve the brain, including alterations in coagulation factors, enhancing the risk of stroke, as well as trophic effects on the reproductive organs, resulting in increased risks for breast and endometrial cancer (10, 11). If regulation of apoE expression is indeed a critical component of the mechanisms mediating neuroprotective responses to estradiol-17ß, direct targeting of apoE regulation in the brain might mimic the beneficial central effects of this hormone without the adverse risks associated with conventional HRT. Such an approach seems at least potentially feasible, because the receptor systems mediating the effects of estrogens on central apoE synthesis may well be different from those found in nonneural estrogen target organs. Thus, estradiol-17
, an estrogen with weak systemic hormonal activity, is fully capable of inducing apoE synthesis and release in mouse cerebral cortex and cultured glial cells (30, 31). As a better understanding of the molecular mechanisms underlying the effects of estrogen on apoE expression evolves, it may be possible to identify agents that will selectively up-regulate apoE expression in the brain with no significant adverse effects on tissues elsewhere in the body.
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Received April 2, 2004.
Accepted for publication April 7, 2004.
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4 is associated with rapid progression of multiple sclerosis. Neurology 57:853–857-1 antichymotrypsin gene in sporadic Parkinson disease. Am J Med Genet 114:446–449[CrossRef][Medline]
4 and testosterone interact in the risk of Alzheimer’s disease in men. Int J Geriatr Psychiatry 17:938–940[CrossRef][Medline]
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