ReviewProtective actions of sex steroid hormones in Alzheimer’s disease
Introduction
As expertly described in the accompanying review articles, sex steroid hormones are potent regulators of neuron survival in multiple CNS regions and across a variety of circumstances ranging from normal development to neural injury. A compelling, and as yet largely unrealized, promise of sex steroid hormones is the translation of their neuroprotective properties into efficacious strategies for the treatment and or prevention of age-related neurodegenerative disorders such as Alzheimer’s disease (AD). Despite this unfulfilled therapeutic potential, abundant experimental, epidemiological and clinical evidence suggest that neural actions androgens, estrogens, and perhaps even progestogens can reduce the risk for AD.
AD is an age-related neurological disease that is the leading cause of dementia. Neuropathologically, AD is characterized by brain region-specific deposition of β-amyloid protein (Aβ) which creates senile plaques, hyperphosphorylation of the cytoskeletal protein tau that forms lesions called neurofibrillary tangles and neuropil threads, glial activation which is associated with inflammatory responses, and both synaptic and neuronal loss [3], [37], [139], [140], [196]. Although the mechanisms of AD pathogenesis remain to be fully resolved, the leading hypothesis posits that the disease is initiated and driven by prolonged elevation of Aβ levels [140]. Aβ is a proteolytic byproduct of the metabolism of amyloid precursor protein, a widely expressed protein with numerous functions ranging from axonal transport to gene transcription [336]. As a consequence of amyloid precursor protein expression, Aβ is normally found as a soluble protein at low levels in fluids and tissues throughout the body. In theory, alterations in either the production or clearance of Aβ that sway Aβ homeostasis towards increased neural levels will promote the development of AD [140]. The accumulation of Aβ encourages its abnormal assembly into oligomeric species that exhibit an altered structural conformation and can induce a range of neurodegenerative effects [136]. Consequently, enormous effort has been expended on identifying factors that regulate Aβ accumulation and or affect its neurodegenerative properties. One such class of factors is sex steroid hormones.
In this review, we will discuss the neuroprotective properties of sex steroid hormones as they relate to AD pathogenesis, focusing largely on their effects on Aβ accumulation and its associated neurodegeneration. Estrogens are the most thoroughly studied steroid hormones in terms of AD. We will cover the epidemiological and clinical evidence that suggests depletion of ovarian hormones at menopause increases the risk of AD in post-menopausal women, a danger some studies suggest may be mitigated by estrogen-based hormone therapy (HT). Consistent with a protective role against AD, experimental studies demonstrate that estrogens not only reduce neuron loss induced by AD-related insults but also act to reduce Aβ levels. However, in the Women’s Health Initiative (WHI) trial, the most exhaustive clinical evaluation of HT thus far, HT was associated with increased rather than decreased risk of AD. Analysis of experimental work reveals several key limitations of estrogen’s neuroprotective actions that may contribute to this clinical observation, including loss of neural estrogen responsiveness with age and interactions with progestogens that may limit estrogen neuroprotection. A more recent and still emerging literature suggests a parallel relationship in men with their primary sex steroid hormone, testosterone. That is, normal age-related testosterone is associated with increased risk of AD in aging men. Like estrogens, androgens also exert neuroprotective properties relevant to AD, including promotion of survival in neurons challenged with AD-related insults and reduction of Aβ levels. Finally, we consider future directions in this field, emphasizing the clinical potential of sex steroid hormones in prevention rather than treatment of AD and the emerging promise of selective estrogen receptor and androgen receptor modulators.
Section snippets
Menopause, hormone therapy, and Alzheimer’s disease
Converging lines of evidence indicate a potentially important role of estrogens in regulating AD pathogenesis. Preliminary clues suggesting this possibility stemmed from reports of sex differences in AD risk, with women showing higher prevalence and incidence. Although sex differences in AD are difficult to interpret due to gender differences in life expectancy, many studies of various cohorts indicate that women are at greater risk of AD [9], [17], [39], [93], [101], [137], [180], [221], [281]
Estrogen neuroprotection and Alzheimer’s disease insults
An established neural action of estrogens that may contribute to a protective role against AD is promotion of neuron viability. Estrogen is neuroprotective against a variety of insults in several cell culture and rodent paradigms of injury and neurodegenerative disease. Of particular interest is the ability of estrogen to protect against neuronal loss induced by Aβ, which is thought to be primary neurodegenerative agent in AD. Reports from several groups demonstrate that estrogen can protect
Estrogen regulation of β-amyloid accumulation
In addition to increasing neuronal resistance to AD-related insults, estrogen may also protect against AD by preventing the key initiator of AD pathogenesis, accumulation of Aβ. Steady state levels of Aβ are influenced by opposing pathways of Aβ production and Aβ clearance, both of which appear to be regulated by estrogen. Estrogen regulation of Aβ was first suggested by cell culture experiments focused on Aβ production. Early studies demonstrated that estrogen modulates processing of amyloid
Aging effects on estrogen responsiveness
Whether the described neuroprotective effects of estrogen prove to have therapeutic relevance to age-related neural diseases including AD will depend in part on the brain’s responsiveness to estrogen with advancing age. One of the primary criticisms of WHIMS and other clinical studies of estrogen-based HT is that the intervention may have been initiated beyond a critical window of opportunity [118], [265], [276]. This notion refers to the possibility that the aging brain age may lose
Progesterone interactions with estrogen in regulation of Alzheimer’s disease
Estrogen actions must also be considered with respect to the second major class of ovarian hormones, progestogens. Progesterone has long been recognized as a regulator of estrogen, particularly in the female reproductive system (reviewed in [130]), where it often antagonizes estrogen action. Clinically, progestogens are typically a key element of HT that are thought to minimize deleterious effects of estrogen. Perhaps most importantly, in experimental paradigms progesterone can inhibit human
Age-related androgen depletion and Alzheimer’s disease
In parallel to the relationships between age-related estrogen loss in women and increased AD risk, testosterone is depleted as a normal consequence of aging in men and is linked with elevated risk of AD. As discussed above, a significant biological event in women that contributes to the role of aging in AD is menopause and the resultant loss of the sex steroid hormones estrogen and progesterone. Although men do not experience menopause per se (i.e., a cessation of reproductive ability, nearly
Testosterone neuroprotection and Alzheimer’s disease insults
One beneficial action of androgens that is hypothesized to contribute to a role in reducing risk of AD is neuroprotection. Androgens are established promoters of neuron viability during neural development as well as in adult brain following mechanical injury and disease-related toxicity. One target of androgen neuroprotection is motorneurons following axotomy [178]. In this paradigm, testosterone treatment accelerates the rate of nerve regeneration and attenuates neuron loss [164], [178], [177]
Testosterone regulation of β-amyloid accumulation
In addition to classic neuroprotective actions, androgens may also protect the brain from AD by regulating accumulation of Aβ. Initial work suggesting a relationship between androgens and Aβ came from a small study evaluating men treated with anti-androgen therapies for prostate cancer. Gandy and colleagues found that within several weeks following initiation of anti-androgen therapy (consisting of leuprolide and flutamide), circulating levels of testosterone and E2 were largely depleted
Emerging strategies of hormone-related therapies in Alzheimer’s disease
As reviewed in this article, there are numerous neuroprotective actions of estrogens and androgens that have direct relevance to AD pathogenesis and compelling potential to prevent and possibly treat the disease. However, the promise of estrogen-based and androgen based HTs in reducing AD risk have yet to be realized. As findings and directions from clinical and basic science research become increasingly integrated, it is anticipated that critical parameters affecting HT efficacy will be
Acknowledgments
This work was supported by NIH Grants AG026572 and AG23739. JCC was supported by NIH Grant F31NS059174.
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