ReviewAndrogen regulation of β-amyloid protein and the risk of Alzheimer's disease
Introduction
Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects over four and one half million people in the United States alone, a number that is projected to grow with the aging of the population (Brookmeyer et al., 1998, Hebert et al., 2003). Advancing age is the most significant risk factor for the development of AD (Evans et al., 1989, Jorm et al., 1987, Rocca et al., 1986), however what age-related changes underlie this effect remain uncertain. In this review, we discuss recent work from our laboratory and others suggesting that one normal age-related change that may contribute to the risk of AD in men is testosterone loss. Further, we suggest that the mechanism by which androgen depletion increases risk of AD in men involves recent evidence that androgens regulate accumulation of β-amyloid (Aβ), perhaps the key event in AD pathogenesis.
With advancing age, men experience a significant decrease in circulating levels of testosterone (Morley et al., 1997, Swerdloff and Wang, 1993). The decline in total testosterone levels begins in the thirties and progresses at an annual rate between 0.2% and 1% (Feldman et al., 2002, Gray et al., 1991). Due to an age-related increase in sex hormone binding globulin (SHBG) at an annual rate of 1.1–1.6% (Feldman et al., 2002, Gray et al., 1991, Harman et al., 2001, Purifoy et al., 1981, Vermeulen et al., 1996), levels of bioavailable testosterone decrease at a higher rate (2–3% per year) than total testosterone (Feldman et al., 2002, Gray et al., 1991, Muller et al., 2003). While age changes in circulating DHT levels are not consistently reported (Feldman et al., 2002, Gray et al., 1991), decreases in other androgens including DHEA and androstendione are observed with increasing age in men (Feldman et al., 2002, Gray et al., 1991, Muller et al., 2003, Vermeulen et al., 1996). The age-associated decrease in testosterone is not paralleled by changes in estradiol levels, which decrease slightly or not at all in aging men (Davidson et al., 1983, Muller et al., 2003, Vermeulen et al., 1996).
Normal age-related testosterone depletion has been associated with functional impairments in androgen-responsive tissues, including bone, muscle, and heart (Baumgartner et al., 1999, Burger et al., 1998, Ferrando et al., 2002, Jones et al., 2003, Meier et al., 1987, Sheffield-Moore and Urban, 2004). Dysfunction and disease due to age-related testosterone loss has been collectively recognized as a clinical syndrome termed ‘androgen deficiency in aging males’ (Morley, 2001). Since the brain is also an androgen responsive tissue, it may be susceptible to age-related androgen loss. Although studies have reported alterations in mood, libido, and cognition resulting from androgen depletion (Gooren, 2003, Kaufman and Vermeulen, 2005, Morley, 2001, Swerdloff and Wang, 1993, Swerdloff and Wang, 2002), the full range of consequences of age-related testosterone loss on the brain remain incompletely defined.
Circulating levels of hormones generally parallel tissue levels, however factors such as sex hormone binding globulin, hormone transport across the blood–brain barrier, and the presence of steroid converting enzymes in brain suggest that brain levels of hormones may vary from what is observed in blood (Manni et al., 1985, Pardridge, 1985, Pardridge, 1986). Recent work from our lab was the first to examine age-related changes in brain levels of testosterone in men. Using neuropathologically normal human postmortem tissue we found a robust decrease in brain levels of testosterone with advancing age that appeared to reach minimal values in men over 80 years of age (Rosario et al., 2004). Consistent with prior observations in circulating levels, we observed no significant change in brain levels of estradiol with increasing age in men (Rosario et al., 2004). The decrease in brain levels of androgens suggests the possibility that beneficial neural actions of androgens may be compromised during aging, resulting in increased risk of neural dysfunction and disease, including AD.
Testosterone and its active metabolite dihydrotestosterone (DHT) have several important actions in the brain. Androgen actions are mediated in part via activation of androgen receptors (AR), which are localized in many brain areas including regions important for learning and memory such as hippocampus and amygdala (Kerr et al., 1995, Simerly et al., 1990, Tohgi et al., 1995). Beneficial actions of androgens in the brain include stimulation of neuronal differentiation, maintenance of neuronal morphology, and promotion of synaptic density (Beyer and Hutchison, 1997, Leranth et al., 2004, Marron et al., 2005, Matsumoto, 1997). For example, studies of hippocampus in male rats show a significant decrease in the density of spine synapses following gonadectomy (GDX) (Kovacs et al., 2003, Leranth et al., 2003), an effect reversed by replacement with either testosterone or DHT (Kovacs et al., 2003, Leranth et al., 2003). In addition to androgen actions in neurons, testosterone has also been found to down-regulate astrogliosis (Day et al., 1998).
Another beneficial neural action of androgens is regulation of neuron viability during developmental apoptosis (Lund et al., 2000, Nordeen et al., 1985, Nuñez et al., 2000) and in adult brain following toxic challenge. Neuronal cell culture studies have revealed neuroprotective effects of androgens against serum deprivation (Brooks et al., 1998, Hammond et al., 2001), Aβ toxicity (Pike, 2001, Zhang et al., 2004, Nguyen et al., 2005), and oxidative stress (Ahlbom et al., 2001). In animal models, testosterone and DHT have been found to accelerate the rate of cranial nerve regeneration (Yu, 1982, Yu and Srinivasan, 1981) and attenuate motor neuron loss following axotomy (Yu, 1989). Similarly, following facial nerve crush in male hamsters, testosterone increased the rate of axonal growth and functional recovery (Kujawa et al., 1991, Kujawa et al., 1989). In addition, androgens have also been found to protect against toxic insult in hippocampus, a brain region vulnerable to neurodegenerative effects of AD. For example, Azcoitia et al. (2001) found that androgen depletion resulting from GDX of adult male rodents increased neuron loss in the hilus of the dentate gyrus following excitotoxic lesion, an effect that was significantly attenuated by acute treatment with testosterone but not DHT. However, Ramsden et al. (2003a) found that extended DHT treatment in GDX male rats significantly blocked the increased hippocampal neuron death caused by the excitotoxin kainate. Because AR levels decrease following GDX, prolonged rather than acute androgen exposure may be necessary for neuroprotection since it allows for restoration of AR expression and consequently AR-dependent signaling (Ramsden et al., 2003a). Although acute treatment with the DHT metabolite 3α-androstanediol can protect against excitotoxin-induced seizures (Frye and Reed, 1998), we found that neuroprotection afforded by long-term DHT treatment was not associated with a decrease in either the latency or severity of kainate-induced seizure (Ramsden et al., 2003a). Thus, available evidence suggests that androgens can afford neuroprotection through a variety of pathways, including both estrogen and androgen pathways.
Section snippets
Androgens and cognition
Androgens are known to affect some aspects of cognition including spatial abilities (Gouchie and Kimura, 1991, Janowsky et al., 1994) and verbal fluency (Alexander et al., 1998). Low levels of androgens have been associated with impaired cognitive performance in some but not all studies (Haren et al., 2005, Moffat et al., 2002). Men with a relatively higher free testosterone index performed better on visual and verbal memory tasks and exhibited better long-term memory (Barrett-Connor et al.,
Androgen regulation of β-amyloid
With a relationship between age-related testosterone depletion in men and increased risk for AD reasonably well established, a critical issue is how androgen loss promotes AD pathogenesis. Perhaps the most likely possibility is through regulation of β-amyloid (Aβ) accumulation, which is widely believed to be the critical initiating step in AD pathogenesis (Hardy and Selkoe, 2002). As discussed below, evidence from our lab and others suggest that androgens function as negative endogenous
Mechanism of androgen regulation of Aβ
Beneficial actions of androgens such as neuron viability and modulation of Aβ levels support the hypothesis that age-related androgen depletion may increase the risk of developing AD. As previously discussed, several studies have identified androgens as endogenous regulators of Aβ (Gandy et al., 2001, Gouras et al., 2000, Gillett et al., 2003, Ramsden et al., 2003b, Rosario et al., 2006). The mechanism(s) by which androgens regulate Aβ is not known, but presumably involves one or more of three
Conclusions and future directions
In this review, we have discussed recent evidence from a number of different research groups, including our own, that collectively indicate a significant relationship between normal, age-related testosterone depletion in men and increased risk for the development of AD. Because androgens exert a variety of beneficial actions in brain, androgen loss may negatively impact the aging brain and increase its vulnerability to age-related neurodegenerative diseases by a variety of mechanisms, including
Acknowledgments
This work was supported by grants from the NIA (AG23739; CJP) and NINDS (NS52143; ERR).
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2020, Handbook of Clinical NeurologyCitation Excerpt :Low circulating levels of biologically active testosterone in the aging male could be deleterious to the brain, though definitive studies that would guide clinical practice are lacking. Several observational studies establish that low testosterone either in the brain (Rosario et al., 2004) or in the systemic circulation (reviewed in Hogervorst et al., 2001; Moffat et al., 2004; Rosario and Pike, 2008; Chu et al., 2010; Verdile et al., 2014) are associated with increased dementia and AD risk, as was also seen in a meta-analysis (Lv et al., 2016). These observations, combined with a small RCT of androgen treatment in men with AD (Cherrier et al., 2005), suggest a protective role for androgens in AD, though RCTs of androgen treatment in older men have shown cognitive improvement in some (Cherrier et al., 2001; Wahjoepramono et al., 2016) but not all (Vaughan et al., 2007; Huang et al., 2016) trials.
The role of extracellular matrix metalloproteinase inducer on the action of dihydrotestosterone against the cellular damage induced by Aβ<inf>42</inf>
2019, Molecular and Cellular EndocrinologyCitation Excerpt :This improvement in the effect of DHT on CD147 expression indicated that the decrease of CD147 in GDX rats might be due to the lower levels of androgens. Androgens play a role mainly through the following three ways: direct actions through AR-dependent pathways, indirect actions through estrogen pathways by testosterone aromatization to estradiol, and indirect actions through gonadotropin pathways by testosterone modulation of the hypothalamic-pituitary-gonadal axis (Rosario and Pike, 2008; Drummond et al., 2009). Because of the expression of the aromatase enzyme in the male hippocampus (Hojo et al., 2004; Ishii et al., 2007), castrated rats were administered DHT, a non-aromatizable androgen, to avoid the estrogen actions in our study.