Neurodegenerative Disease: Roles for Sex, Hormones, and Oxidative Stress

Abstract

Neurodegenerative diseases cause severe impairments in cognitive and motor function. With an increasing aging population and the onset of these diseases between 50 and 70 years, the consequences are bound to be devastating. While age and longevity are the main risk factors for neurodegenerative diseases, sex is also an important risk factor. The characteristic of sex is multifaceted, encompassing sex chromosome complement, sex hormones (estrogens and androgens), and sex hormone receptors. Sex hormone receptors can induce various signaling cascades, ranging from genomic transcription to intracellular signaling pathways that are dependent on the health of the cell. Oxidative stress, associated with aging, can impact the health of the cell. Sex hormones can be neuroprotective under low oxidative stress conditions but not in high oxidative stress conditions. An understudied sex hormone receptor that can induce activation of oxidative stress signaling is the membrane androgen receptor (mAR). mAR can mediate nicotinamide adenine dinucleotide-phosphate (NADPH) oxidase (NOX)-generated oxidative stress that is associated with several neurodegenerative diseases, such as Alzheimer disease. Further complicating this is that aging can alter sex hormone signaling. Prior to menopause, women experience more estrogens than androgens. During menopause, this sex hormone profile switches in women due to the dramatic ovarian loss of 17β-estradiol with maintained ovarian androgen (testosterone, androstenedione) production. Indeed, aging men have higher estrogens than aging women due to aromatization of androgens to estrogens. Therefore, higher activation of mAR-NOX signaling could occur in menopausal women compared with aged men, mediating the observed sex differences. Understanding of these signaling cascades could provide therapeutic targets for neurodegenerative diseases.

Oxidative stress is an imbalance between damaging pro-oxidants, such as reactive oxygen species (ROS), and antioxidants. This dysregulation can lead to cellular dysfunction and cell loss. Oxidative stress is a common feature in several neurodegenerative diseases, such as Alzheimer disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS) (1, 2). Notably, sex differences are observed in each of these diseases (Fig. 1). Currently, only palliative care is available as treatment for these neurodegenerative diseases. Thus, understanding sex-specific disease processes may lead to potential individualized therapeutic targets.

Figure 1.

Several neurodegenerative diseases that are associated with oxidative stress exhibit sex differences. Men have a higher incidence of Parkinson disease, and amyotrophic lateral sclerosis, while Alzheimer disease and multiple sclerosis shows a greater incidence in women. Huntington disease affects men and women equally.

Alzheimer disease accounts for 60% to 80% of dementia cases, and in the United States there are currently 5.8 million individuals with AD aged 65 and older (3). Women with dementia/AD outnumber men 2 to 1 and suffer more severe pathology due to neurofibrillary tangles and faster cognitive declines. Common AD pathological features include Amyloid β (Aβ) and Tau, which can be recapitulated in several rodent models, such as the 3XTg-AD mice (4). Studies that have measured Aβ disposition in these mice reported finding 3 to 4 times more in the hippocampi and amygdalae of 6- and 12-month-old female mice than in males of the same age (4). Additionally, in rodents, depletion of estrogen and progesterone after ovariectomy was associated with increased memory deficits and accelerated AD pathology compared with their sham-treated (intact) counterparts (4-6). Clinical studies that measured AD biomarkers with positron emission tomography found higher densities of Tau tangles in women (4). Apoliproteins E are involved in cholesterol homeostasis and the corresponding gene APOE is polymorphic within the central nervous system. The well-known E4 variant is the largest genetic risk factor for AD (7-10), with studies reporting some variation in risk level based on ethnicity (11). The aforementioned age and sex risk factors can converge onto the genetic risk factor, placing particular populations at even greater risk (12). Females carrying the APOE4 allele (major genetic risk factor for AD that is involved in cholesterol homeostasis) have more rapid cognitive declines and score worse on memory tasks than APOE4-carrying males (4, 6, 13, 14). A clinical study examining human brains found a significantly higher percentage of women carrying the APOE4 allele and had higher levels of AD pathology in the temporal and neocortical regions (15). Interestingly, sex hormones influence AD pathology based on evidence from studies comparing AD incidence in women that had undergone surgical and natural menopause (15). Women classified under surgical menopause suffered a greater AD pathology burden compared with women undergoing natural menopause, due to AD symptoms occurring at a younger age, and they exhibited higher density of Tau tangles and Aβ compared with men (15). In contrast, studies investigating the male sex hormones, androgens, have found a relationship with low testosterone levels and AD pathology (5, 6). In postmortem neuropathology studies, it was determined that AD was associated with low estrogens in women and low androgens in men (6, 16). In addition, in early AD, Aβ levels were inversely correlated with brain testosterone levels, supporting the hypothesis that decreased testosterone in men may increase the development of AD (6). However, other studies have not shown this association, as evidenced by a lack of cognitive improvement in older men when given testosterone supplements in the Testosterone Trials (TTrials) (17). Alarmingly, testosterone can increase oxidative stress (18-20) and oxidative stress–associated conditions (21), facilitating testosterone’s negative effect on cognition (22) due to the negative effects of androgens in an oxidative stress environment (18-20, 23-25).

Parkinson disease is the second most common neurodegenerative disorder, characterized by an α-synuclein (αS) pathology and deficiency of dopaminergic neurons in the substantia nigra (26-28). PD cases typically occur sporadically with only ~10% of cases associated with genetic mutations (26, 29). While men have twice the risk of developing PD and have more severe onset symptoms than women, women have a higher mortality rate and overall faster disease progression (26-29). Women are more likely to develop postural instability leading to increased falling with PD progression, whereas men develop a frozen gait and camptocormia (an axial postural deformity that occurs when standing) (26). Preclinical studies have used the tetramer abrogation mouse model known as the 3K transgenic strain (30, 31). The 3K mice mimic PD pathology by showing a progressive loss of aggregate resistant tetramers and an excess of αS monomers that accumulate, leading to various cortical and dopaminergic neurite loss (30, 31). The 3K mice exhibit significantly poorer performance in motor behavioral tests than regular wild-type mice (31). The study also reported sex differences, in which the 3K male mice performed more poorly across all motor tests as compared with the female mice; this difference was attributed to increased estrogen in female mice (31). Indeed, premenopausal estrogen has been associated with decreased oxidative stress generation via one of the main cellular oxidative stress generators, NADPH oxidase (NOX), and the loss of estrogen during menopause results in increased oxidative stress and PD risk (32). However, postmenopausal women continue to produce androgens (testosterone, androstenedione) (33-39), which can also increase NOX activation (25, 40, 41).

Amyotrophic lateral sclerosis is caused by a progressive degeneration of motor neurons in the brain and spinal cord, leading to an inability to perform voluntary motor movements that usually leads to death within 2 to 5 years (42). The main 2 factors that impact ALS risk are diet and sex: men are 2 to 3 times more susceptible to ALS and exhibit a more severe progression than premenopausal women (42). Postmenopausal women are just as likely to develop ALS with a similar progression to men (42). This observation supports the hypothesis that sex hormones may be key contributing factors to ALS occurrences (42). Preclinical work has focused on the use of a mouse strain, the SOD1 G37R strain, which exhibits ALS symptoms with a progressive loss of neuromuscular junctions in early onset, leading to a universal degeneration of motor axons and axonal sprouting within the motor cell (43-45). Interestingly, female SOD1 mice have a higher level of axonal sprouting than male SOD1 mice, which was associated with worsened grip strength, higher neuromuscular junction degeneration, and decreased motor neuron survival (45).

Multiple sclerosis is a disease that involves both the immune system and central nervous system, both of which are associated with sex differences (46). Women are more susceptible to MS and have an earlier onset, while men tend to have a longer MS progression and suffer greater cognitive decline if they have the APOE4 allele (46). The female to male ratio varies depending on geographic region from 2:1 to 3:1 (46), with a speculative rise in women attributed to gene-environment interactions or epigenetic factors (46). In animal models, astrocytes regulating the course of inflammation may play a key role in sex differences (28). Male and female mice have different neuroinflammatory responses that may explain how each sex adapts to the symptoms of MS (28). Usually, there is a higher degree of inflammation in women but more neurodegenerative lesions in males (46).

Sex Hormones

Sex hormones, such as androgens (eg, testosterone) and estrogens (eg, 17β-estradiol), are well-studied hormones that can have diverse and systemic effects via their widely distributed cognate receptors. These diverse effects range from cellular protection via their anti-oxidative stress properties (47, 48) to cellular toxicity via their pro-oxidative stress properties (18-20, 23, 24). In the brain, sex hormones impact various signaling pathways, including catecholaminergic (dopamine, norepinephrine) neurons and basal forebrain cholinergic (acetylcholine) systems (49), which regulate many behavioral functions (eg, cognitive function, motor control, emotion, neuroimmune responses, social behaviors, arousal, and responsiveness to environment or stressors) (50-54). The impact of sex hormones on these neurotransmitter pathways could mediate sex differences in several neurodegenerative diseases (24).

Sex hormones are also known as gonadal hormones, as they are typically produced in the gonads, with additional generation in the brain, adrenal glands, and other tissues (49, 55-57). Testosterone, the major male sex hormone, is metabolized into 17β-estradiol and dihydrotestosterone (DHT) through aromatase and 5-alpha-reductase, respectively, or into androstenedione by CYP3A4. Androstenedione can undergo further metabolism with aromatase, ultimately forming 17β-estradiol or 5-alpha-reductase producing 5-alpha-androsterone (55, 58). 17β-estradiol, the major female sex hormone originating from the ovaries, can be metabolized to estrone, converted to estriol, and excreted in the urine. Metabolic interconversions of circulating estrogens are constantly in flux. Production of androgens and estrogens are regulated via negative feedback regulation that acts at the level of the brain, pituitary gland, and gonads (59).

Sex hormones are present throughout the lifespan of an organism, including prenatal development, puberty, and aging (60-63). The aging of the reproductive function is characterized by a loss of gonadal function. For men, this occurs as a slow progressive decline in tandem with a decrease in testicular function over time, resulting in a gradual decrease of testosterone that is approximately 1% testosterone loss/year of age after 30 years of age (ie, andropause) (64-66). In women, this change is a more rapid decline of sex hormones compared with that in men, occurring generally around 50 years of age and resulting in a precipitous decrease of estrogen (ie, menopause). In addition to decreasing gonadal hormone levels in males and females, aging can also alter the gonadal hormone profiles. Generally, estrogen is higher in women than in men. However, aged men have higher estrogen levels than aged women due to the aromatization of testosterone (16, 67). Additionally, postmenopausal women are in an androgenic state, as ovaries in postmenopausal women continue to produce androgens (testosterone, androstenedione) (33-39), irrespective of the loss of ovarian estrogen production (57, 68-74). Although loss of estrogen during the postmenopausal state is generally associated with increased risk for neurodegeneration in women, androgens may also play a role, as postmenopausal women exhibit an androgen sex hormone profile.

Sex Chromosome Complement

At the physiological level, the sexual dimorphism of aging often involves changes in sex hormone levels, regulated by the endocrine system, which affects the systemic homeostasis and the interplay between cells and organs (75). At the genetic level, sexual dimorphism is shown in biological sex differences that are predetermined by sex chromosome complement. Mammalian females possess 2 copies of X chromosomes (XX) while the male counterparts possess an X copy and a Y copy (XY). Different genetic makeups lead to different physiological makeups, with the presence or absence of testes or ovaries in males and females, resulting in the prevalence of one sex hormone over another (76).

On average, the life expectancy for women is longer than that for men (77, 78), which is true throughout the animal kingdom (79). Genetic manipulation creating mice (“four core genotype”: FCG) with either XX or XY chromosomes, each with either ovary or testes, allows investigators to uncouple the effects of sex chromosomes and sex hormones. The XX chromosome mice have a longer lifespan compared with XY mice; the presence of ovaries lengthens the lifespan of XX mice but bears no effect on XY mice (80). This leads to the hypothesis that gonadal hormones have protective effects against aging in the presence of a second X chromosome (80).

Sexually dimorphic genetic factors (sex chromosomes X and Y) can readily and differentially influence the makeup and activity of male and female brains, prior to the expression of gonadal hormones (81). The FCG model demonstrates that sex chromosome genes directly influence sexual dimorphism in behaviors, gene expression, and susceptibility to diseases (82-85). As a result, it is reasonable to speculate that genes on sex chromosomes can influence the states of neurological pathology at the molecular level, such as neurotransmitter biosynthesis, central nervous system enzyme expression (86), and synaptic transmission (87).

Abnormalities in sex chromosome complement contribute to neuropsychiatric disorders. For instance, the lack of an X chromosome is associated with Turner syndrome in females as well as susceptibility to autism in males (88) and attention-deficit hyperactivity disorder (ADHD) (89); an extra Y chromosome is found in children diagnosed with ADHD (90). An extra X chromosome may be linked to executive and behavioral dysfunctions in children (91). However, the relationship between sex chromosome complement and neurodegeneration is unclear.

Several discoveries have been recently made and provide new venues to study sex-chromosome-specific neural impairments. A 2019 study using sex-stratified genome-wide association studies of deceased patients diagnosed with AD found that the scope of the genetic risk factor for AD expanded beyond the APOE gene region and into the sex-specific chromosome 7 (rs34331204) associated with neurofibrillary tangles only in males (13). X chromosome aneuploidy in the hippocampus and cerebral cortex of AD patients was increased from 1.32% in controls to 2.79% in AD patients, although such low levels of occurrence are not likely to play a major role in AD incidence (92). Similarly in PD, the chromosomal culprits of tremor and Parkinsonism are associated with sex chromosomes (93). The Y chromosome gene, SRY (Sex-determining Region found on the Y chromosome) is suspected to be involved in PD pathology (94, 95). SRY protein expression has been found in the hypothalamus, frontal and temporal cortex (96, 97), midbrain (98), and ventral tegmental area (99) of adult men. SRY gene products regulate the expression of other proteins involved in dopamine biosynthesis and metabolism (99). SRY is upregulated in PD animal and cell culture models while the suppression of SRY expression mitigates the neurodegeneration and motor impairments (94). On the other hand, an X-chromosome-wide association study in 2021 revealed a potential role of X chromosomes in PD pathology. There are at least 2 genome-wide significant loci on the X chromosome, rs7066890 and rs28602900, that are associated with PD risk (100).

Increased sex chromosome aneuploidy is often associated with aging (101) neurodegeneration, including AD (92). Loss of both sex chromosomes is age-dependent (102). It is hypothesized that the loss of the Y chromosome is a marker of age-related effects (103). Mounting evidence has also pointed toward the abnormal frequency of X chromosome aneuploidy contributing to AD. Together, these findings suggest that sex chromosome aneuploidy may contribute to the pathology of sex-specific or sex-biased neurodegeneration and brain aging.

Oxidative Stress

At low to moderate levels, ROS act as important molecules in signal transduction pathways, promote cell differentiation, and play an important role in host immune defense against pathogens (104, 105). Oxidative stress is defined as an imbalance between oxidants and protective antioxidant systems due to an excess in ROS levels (106) leading to posttranslational chemical modifications to macromolecules (eg, nucleic acids, proteins, lipids) causing cellular damage (107-109). The brain is particularly vulnerable to oxidative stress because of its high oxygen demand, relatively low concentration of antioxidants, and high concentration of easily oxidized polyunsaturated fatty acids and redox-active metal ions (110). Therefore, oxidative stress has been proposed as an important mechanism in neurodegenerative diseases such as AD, PD, ALS, and MS (1, 2, 111). Of note, prominent sex differences exist in oxidative stress, as females have overall lower levels of ROS-induced damage and higher antioxidant enzymes (24, 41, 112, 113). Sex differences have also been observed in one of the main oxidative stress signaling pathways involving interactions between NOX and angiotensin II (114, 115).

Common Oxidative Stress Pathways

NADPH oxidase (NOX) is an enzyme complex that catalyzes electron transfer across the plasma membrane from the substrate, NADPH, to oxygen, thus generating superoxide radicals (116, 117). NOX serves as a prominent source of ROS in the central nervous system and its isotypes are widely distributed across brain, especially in key structures involved in learning and memory (118, 119). Studies have revealed sex differences in NOX in vitro (120, 121) and in vivo (122, 123), with males having overall higher NOX levels. Van Kempen et al discovered that female mice with experimentally induced “postmenopause” displayed marked differences in the distribution of the cytoplasmic and plasmalemmal NOX p47^phox subunit in hypothalamic neurons compared with males and control females (122). Protein expression of Nox1 and Nox2 has been observed to be higher in males whereas Nox4 was higher in females (121). We previously discovered that NOX signaling can be modulated by androgens (25), suggesting that NOX-induced oxidative stress may be a potential mechanism in sex differences observed in neurodegenerative diseases.

Angiotensin II (ANG II) is the main effector peptide of the central renin angiotensin system, and its effects are mediated by angiotensin type I and type II type receptors (A1TR; A2TR). The primary oxidative stress mediated effects of ANG II are via A1TRs. Activation of AT1R turns on a redox-dependent pathway that stimulates NOX, leading to increased ROS generation. Therefore, a feed forward stimulation of NOX and ANG II/A1TR signaling exists in which increased NOX-derived ROS can regulate A1TRs (114, 124, 125). Estrogen has a protective role by reducing A1TR expression and ANG II-induced ROS production (126-128). Dean et al discovered that upon reducing estrogen levels via ovariectomy in female rats, central AT1R expression increased and the effects were reversed by estrogen treatment (126). Interestingly, androgens increased ANG II activation (129, 130). Similarly, we observed androgens increased ANG II release in the hippocampus and substantia nigra while estrogens decreased ANG II release in the hippocampus using sniffer cells (CHO cells that express A1TR and fluoresce in response to ANG II) placed on the surface of a brain slice (Figs. 2 and 3). Interestingly, androgens increased ANG II release via the membrane androgen receptor (mAR), as evidenced by the ANG II release in response to the cell-impermeable androgen, dihydrotestosterone bound to bovine serum albumin (BSA).

Figure 2.

Angiotensin-sensitive sniffer cells placed on the substantia nigra (A) demonstrate increased fluorescence intensity in response to bath application of DHT-BSA to activate mAR in brain slices from male rats. DHT-BSA evoked an 8% increase in fluorescence intensity in AT1R-expressing sniffer cells while direct activation of sniffer cells with exogenous ANG II application produced a 20% increase in fluorescence intensity, suggesting mAR induced ANG II release in the substantia nigra of male rats (B). Sniffer cells did not respond to bath application of vehicle (C) but showed an increase in fluorescence intensity during bath application of 100 nM DHT-BSA (D). Each cell is represented by a different line color. ** = P < 0.01, paired t test. N = 6.

Figure 3.

Representative examples of spontaneous sniffer cell activity in response to bath application of (A) 100 nM DHT-BSA (mAR ligand) or (C) 100 nM 17β-estradiol (estrogen receptor ligand) in brain slice from a female (XX) rat. (B) Bath perfusion of DHT-BSA is associated with increased spontaneous AT1R sniffer cell activity in the hippocampal CA1 region while (D) bath perfusion of 17β-estradiol is associated with decreased spontaneous sniffer cell activity. Each cell is represented by a different line color. * = P < 0.05, ** = P < 0.01 paired t test. N = 10.

Aging has long since been associated with increased oxidative damage, and the oxidative stress theory of aging (131) posits that age-associated functional loss is based on accumulation of oxidative damage to macromolecules (132). Multiple studies indicate that sex hormones can have both neuroprotective and neurotoxic effects (20, 23, 25, 48, 133). Possible mechanisms for sex hormone neuroprotection include anti-oxidative stress properties (134) and oxidative stress preconditioning (23). However, these protective effects of sex hormones appear to be dependent on the status of the cell. Indeed, this phenomenon has been described by Dr. Roberta Brinton as the “healthy cell bias of estrogen,” in which estrogens are protective in cells that are healthy but are damaging in unhealthy cells (135). Our studies extend Dr. Brinton’s seminal work by showing that androgens are also protective in healthy cells but damaging in unhealthy cells (23, 25), especially in cells that have an elevated oxidative stress load. Our research found that an estrogen receptor alpha/beta mechanism mediated the neuroprotective effects of estrogen and testosterone against subsequent oxidative stress insults. In contrast, the neurotoxic effects of androgens and estrogens are less well understood. We observed that a mAR (splice variant of the androgen receptor, AR45) mediated testosterone’s neurotoxic effects in an existing oxidative stress environment, but it is unknown what mechanism is mediating estrogen’s neurotoxic effects in an oxidative stress environment (23). Overall, sex hormones appear to be protective against subsequent oxidative stress insults but in cellular environment with existing oxidative stress they can induce neurotoxicity and increase the risk for neurodegeneration.

Sex Hormone Genomic and Nongenomic Cell Signaling

The exact nature of sex hormonal effects on cell viability is dependent on sex hormone receptors and their cellular signaling cascades. These cascades are activated through either genomic signaling (initiated by cytosolic nuclear hormone receptors that migrate to the nucleus to alter gene transcription) or through a nongenomic signaling (mediated by a membrane-bound hormone receptor). Intracellular nuclear receptors mediate genomic alteration of gene transcription by sex hormones, such as nuclear estrogen receptors (ERα and ERβ) (136-138) and the nuclear androgen receptor (AR) (139, 140) binding to their respective estrogen or androgen response elements.

Estrogens are generally associated with activating prosurvival pathways (141). These pathways include the brain-derived neurotropic factor (BDNF) (142), which is involved in neuronal growth and synaptic plasticity (143), the mitogen-activated protein kinase (MAPK) cascade (144), which mediates cellular differentiation and survival (145), and cyclic adenosine monophosphate (cAMP) (137) activity and cAMP dependent signaling cascades (146). Androgen neuroprotective effects are mostly related to the estrogen-mediated mechanisms due to aromatization of testosterone into 17β-estradiol (141) or metabolism of DHT into 17β-diol (147). However, estrogen-independent mechanisms of androgen neuroprotection have been observed (148), in which androgens via the AR induce activation of extracellular signal-regulated protein kinase (ERK), MAPK, and CREB pathways (149).

Nongenomic signaling of sex hormones can occur. Nongenomic steroid receptor–mediated signaling is understudied compared with genomic sex hormone signaling. Multiple membrane-bound estrogen receptors (mERs) have been identified within the brain within cholesterol-rich lipid rafts in the plasma membrane (150). These mERs include membrane-bound variants of the ERα and ERβ receptors, GPR30 (G protein-coupled estrogen receptor 1; GPER1), and Gq-mER (151). ERα, ERβ, and GPER1 are involved in synaptic formation and function in the hippocampus and cortex through multiple signaling cascades, such as the BDNF pathway (152), caspase 3/7 (153), cAMP, MAPK, PI3 kinase, and protein kinase C pathways (154). In contrast to multiple membrane-associated estrogen receptors in the brain, studies examining the presence and function of mARs within the brain are limited. Recently, Thomas et al summarized 3 mARs of interest which have been observed in the brain: ZIP9, TRPM8, and GPRC6A (155). ZIP9 has been identified in a mouse hippocampal cell line and can induce ERK/MAPK signaling associated synaptic plasticity (156). TRPM8 receptor was found to be localized in lipid rafts (157) and acts as a neuronal somatosensory receptor (158, 159). However, the function of testosterone at TRPM8 receptor is relatively unknown and has only been investigated in the past decade (160, 161), with evidence that there are multiple testosterone-related behaviors affected through this receptor (161). Although GPRC6A was observed in the brain (162), the role of this mAR within the brain and the impact of testosterone is unknown. In addition to these 3 mARs, our laboratory has identified the presence of another mAR, an androgen receptor splice variant (ie, AR45) that is localized to lipid rafts in multiple brain regions (substantia nigra, hippocampus, entorhinal cortex) (163). The function of AR45 is linked with oxidative stress generation (23, 163). These effects are mediated via both the NOX and inositol triphosphate receptor–dependent intracellular calcium (Ca²⁺) activation (25). In addition, to mAR mediating activation of NOX, mAR is also involved in ANG II release (Figs. 2 and 3) that can further activate NOX oxidative stress signaling to result in a feed forward oxidative stress response.

Possible Therapeutic Strategies for Neurodegeneration

Currently, no therapeutic drugs are available for neurodegenerative diseases. Only palliative treatments to address symptoms of the diseases are available. Since sex differences are observed in many neurodegenerative diseases, potential therapeutics could decrease the progression of these diseases by focusing on sex hormone mediated oxidative stress pathways.

Sex hormone modulators, such as agonists and antagonists at the receptor level, can be used to amplify or inhibit sex hormone signaling. Common androgen receptor and estrogen receptor modulators act at genomic nuclear receptors. There are few selective membrane estrogen receptor (G protein-coupled estrogen receptor, GPER) antagonists, such as G15, G36, CIMBA, PBX1, PBX2, and C4PY (164-168). Of these GPER antagonists, only G15 and its derivative G36 have shown efficacy in blocking GPER actions within the brain (169, 170). Similarly, there is only one mAR antagonist, novel small molecule peptidomimetic (D2). D2 has shown efficacy in blocking mAR actions in prostate cancer cells (171), but D2’s impact on mAR within the brain is unknown. In addition, an androgen receptor degrader, ASC-J9, can block genomic and nongenomic signaling by degrading membrane-associated and nuclear androgen receptors that are located within the brain and the periphery (23, 25, 172).

Issues have been noted with estrogen receptor antagonists, in which their actions (agonist or antagonist effects) are region dependent. A common estrogen receptor antagonist, ICI 182 780, acts at ERα/β but in certain tissues it affects the ERα and in other regions it affects ERβ (173, 174). Although ICI 182 780 generally acts as an estrogen receptor antagonist, it can act as an agonist on GPER (175), and thus ICI 182 780 has both antagonistic and agonistic properties. Similar issues have been noted with other ER antagonists, such as tamoxifen and clomiphene, which function differently based on tissue type (173, 174, 176, 177). Thus, the use of sex hormone receptor antagonists may not be beneficial as a therapeutic for neurodegenerative disorders, as these antagonists can have a lack of specificity depending on cell type.

Preclinical and clinical studies overwhelmingly show that males exhibit higher oxidative stress than females (25, 40, 178, 179). However, this does not necessarily mean that males are more vulnerable to neurodegenerative conditions. In fact, the increase in ROS in males, which is closely intertwined with androgens, can lead to preconditioning and eventually, neuroprotection. The prevailing level of oxidative stress determines if androgens will offer neuroprotection or escalate neurodegeneration with higher levels of oxidative stress being worsened by androgens. Since androgens can activate NOX and ANG II/A1TR pro-oxidative stress signaling (114, 124, 125), this pathway may be a potential target for neurodegenerative disease therapeutics.

Increased levels of AT1R and angiotensin-converting enzyme (ACE), the enzyme involved in ANG II activation, have been reported in postmortem AD brain tissue (180). Thus, some researchers have asked the natural question of whether inhibition of ANG II would lead to improvement of AD. A meta-analysis showed that angiotensin receptor blockers (ARBs) had significant benefits compared with placebo on overall cognition and were more effective than antihypertensives (eg, beta-blockers) (181). Another trial found an inverse association between patients placed on ARBs and various dementias (182). Interestingly, different outcomes have been observed in other studies (183-185). Similar to ARBs, inhibitors of angiotensin-converting enzyme have been promising in preclinical trials (186) but have equivocal results in clinical trials. While some studies have reported decreased AD symptoms via inhibition of ANG II (181), others have reported otherwise (30, 183, 184). What is remiss in these trials, which could have contributed to the diverse results, is the failure to evaluate the effects of sex on ANG signaling, and by extension, inhibition.

Sex hormone receptors (eg, mAR) and AT1R can reside within cholesterol-rich lipid rafts in the plasma membrane of cells (25, 150, 163, 187-190). Interestingly, the mAR complexes with NOX in lipid rafts (25), and ANG II can impact NOX trafficking into and out of lipid rafts (191). Therefore, it may be possible to use cholesterol inhibitors, such as statins (192), to decrease both mAR and ANG II mediated oxidative stress and risk for neurodegenerative diseases. Indeed, studies have shown that statins can suppress the production of ROS (193). Although it is unclear what role cholesterol inhibition via statins may have on neurodegenerative disease risk (193-195), some studies have found that lowering cholesterol levels may be beneficial for dementia in aged patients (196) and may decrease AD risk and cognitive impairment (53, 197). Although it remains unclear what role sex plays on the ability of statins to decrease cholesterol (198-201), statins may play possible therapeutic roles in targeting membrane-associated sex hormone receptors and ANG II receptors that can increase oxidative stress generation and increase the risk for neurodegeneration.

Summary

Oxidative stress is a key mediator of neurodegenerative diseases and sex hormone cellular signaling, in which estrogens can decrease oxidative stress and androgens can increase oxidative stress via common signaling cascades (NOX-AT1R). The understudied mAR appears to play a role in NOX-AT1R activation through its effects at both NOX and AT1R, which could make this pathway a viable therapeutic target to slow the progression of oxidative stress–associated neurodegenerative diseases (Fig. 4).

Figure 4.

The membrane androgen receptor (mAR) can increase oxidative stress generation by multiple routes, such as binding to mAR to induce NADPH oxidase (NOX) induced oxidative stress. Also, the mAR can induce the release of ANG II that can bind the AT1R that can increase NOX-induced oxidative stress. The mAR, NOX, and AT1R are present within plasma membrane lipid raft signaling hubs. These lipid raft signaling hubs can further strengthen signaling, resulting in increased oxidative stress generation.

Glossary

Abbreviations

αS

α-synuclein

Aβ

Amyloid β

A1TR

angiotensin type I receptor

A2TR

angiotensin type II receptor

AD

Alzheimer disease

ALS

amyotrophic lateral sclerosis

ANG II

angiotensin II

BDNF

brain-derived neurotrophic factor

BSA

bovine serum albumin

cAMP

cyclic adenosine monophosphate

CREB

cAMP-response element-binding-protein

DHT

dihydrotestosterone

ERα (or β)

estrogen receptor α (or β)

ERK

extracellular regulated protein kinase

GPER

G protein-coupled estrogen receptor

MAPK

mitogen-activated protein kinase

mAR

membrane androgen receptor

mER

membrane-bound estrogen receptor

MS

multiple sclerosis

NOX

nicotinamide adenine dinucleotide-phosphate (NADPH) oxidase

PD

Parkinson disease

ROS

reactive oxygen species

Additional Information

Disclosures : The authors have nothing to disclose.

Data Availability

All data generated or analyzed during this study are included in this published article.