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.

Keywords: AR45; angiotensin; estrogen; membrane androgen receptor; oxidative stress; testosterone.

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.

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.

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.