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 50-70 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. 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 NADPH oxidase (NOX) generated oxidative stress that is associated with several neurodegenerative diseases, such as Alzheimer’s 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 to aged men, mediating the observed sex differences. Understanding these signaling cascades could provide therapeutic targets for neurodegenerative diseases.

Genotype–phenotype correlations in valosin-containing protein disease: a retrospective muticentre study

“…The male predominance in this study might not be attributed to specific population distribution as patients from 24 different countries and from independent families were included. Gender predominance was also reported in other neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and ALS, in which sex hormones might play a role in the cell ability to cope with oxidative stress related with ageing what could be aggravated under pathological conditions 40. Moreover, male predominance has also been described in other muscular dystrophies, such as ANO5 41.…”

Protective Effect of Renin-Angiotensin System Inhibitors on Parkinson’s Disease: A Nationwide Cohort Study

“…Interestingly, the protective effect of BBB-crossing ARBs on PD was more remarkable in female than in male. Sex-specific differences in PD risk have been attributed to various potential mechanisms, including hormonal effects and brain RAS expression ( Sullivan, 2008 ; Rodriguez-Perez et al, 2011 ; Labandeira-Garcia et al, 2016 ; Sumien et al, 2021 ). Moreover, enhanced effectiveness of ARBs in females has been shown in both clinical and experimental studies, according to sex differences in the AT 1 /AT 2 receptor expression ratio ( Okumura et al, 2005 ; Sullivan, 2008 ).…”

Inhibition of the integrated stress response reverses oxidative stress damage-induced postoperative cognitive dysfunction

“…Abundant evidence has revealed the role of oxidative stress damage in the pathophysiology underlying neurodegenerative diseases (Radi et al, 2014 ; Sumien et al, 2021 ). Confounding multi-factorial causes of POCD and oxidative stress are important in the pathogenesis of POCD (Netto et al, 2018 ).…”