Department of Pharmacology & Neuroscience, Center for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Department of Physiology & Anatomy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Endocrinology. 2021 Nov 1;162(11). doi: 10.1210/endocr/bqab185.
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.
神经退行性疾病导致认知和运动功能严重受损。随着人口老龄化的增加以及这些疾病在 50 至 70 岁之间的发病，其后果必然是毁灭性的。虽然年龄和寿命是神经退行性疾病的主要危险因素，但性别也是一个重要的危险因素。性别的特征是多方面的，包括性染色体组成、性激素（雌激素和雄激素）和性激素受体。性激素受体可以诱导各种信号级联反应，从基因组转录到依赖于细胞健康的细胞内信号通路。与衰老相关的氧化应激会影响细胞的健康。在低氧化应激条件下，性激素可以起到神经保护作用，但在高氧化应激条件下则不行。一个研究较少的可以诱导氧化应激信号激活的性激素受体是膜雄激素受体（mAR）。mAR 可以介导烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（NOX）产生的氧化应激，这种氧化应激与几种神经退行性疾病有关，如阿尔茨海默病。更复杂的是，衰老会改变性激素信号。绝经前，女性体内的雌激素比雄激素多。在绝经期间，由于卵巢 17β-雌二醇急剧减少，同时卵巢雄激素（睾酮、雄烯二酮）的产生保持不变，女性体内的这种性激素谱发生了变化。事实上，由于雄激素向雌激素的芳香化作用，老年男性体内的雌激素比老年女性高。因此，与老年男性相比，绝经后女性体内的 mAR-NOX 信号可能会更活跃，介导观察到的性别差异。对这些信号级联的理解可以为神经退行性疾病提供治疗靶点。
