Department of Pharmaceutical Sciences, University of North Texas (UNT) System College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX, United States.
North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, TX, United States.
Front Endocrinol (Lausanne). 2024 Jul 18;15:1420144. doi: 10.3389/fendo.2024.1420144. eCollection 2024.
Sex differences in oxidative stress-associated cognitive decline are influenced by sex hormone levels. Notably, oxidative stress-associated neuronal cell death can be exacerbated through testosterone signaling via membrane androgen receptor AR45, which is complexed with G protein G within plasma membrane-associated lipid rafts. The objective of this study was to elucidate the impact of sex on the expression of AR45 and G in brain regions associated with cognitive function, specifically hippocampus subregions and entorhinal cortex. Additionally, we investigated whether chronic intermittent hypoxia (CIH), an oxidative stressor with sex-specific effects, would modulate AR45 and G expression in these brain regions.
Adult male and female Sprague-Dawley rats were exposed to CIH or normoxia (room air) during their sleep phase for 14 days. We quantified AR45 and G protein expression in various cognition-associated brain regions [dorsal hippocampal CA1, CA3, dentate gyrus (DG), and entorhinal cortex (ETC)] via western blotting. For comparisons, AR45 and G protein expression were also assessed in brain regions outside the hippocampal-ETC circuit [thalamus (TH) and striatum (STR)].
The highest AR45 levels were expressed in the hippocampal CA1 and DG while the lowest expression was observed in the extrahippocampal STR. The highest G levels were expressed in the hippocampal-associated ETC while the lowest expression was observed in the extrahippocampal TH. Females expressed higher levels of AR45 in the hippocampal DG compared to males, while no sex differences in G expression were observed regardless of brain region assessed. Moreover, there was no effect of CIH on AR45 or G expression in any of the brain regions examined. AR45 expression was positively correlated with G expression in the CA1, DG, ETC, TH, and STR in a sex-dependent manner.
Our findings reveal enrichment of AR45 and G protein expression within the hippocampal-ETC circuit, which is vulnerable to oxidative stress and neurodegeneration during cognitive decline. Nonetheless, CIH does not modulate the expression of AR45 or G. Importantly, there are sex differences in AR45 expression and its association with G expression in various brain regions, which may underlie sex-specific differences in cognitive and motor function-associated declines with aging.
氧化应激相关认知衰退中的性别差异受性激素水平的影响。值得注意的是，氧化应激相关的神经元细胞死亡可以通过膜雄激素受体 AR45 与质膜相关脂筏中的 G 蛋白 G 复合物的信号转导而加剧，AR45 是雄激素受体家族的一员。本研究的目的是阐明性别对与认知功能相关的脑区（特别是海马亚区和内嗅皮层）中 AR45 和 G 表达的影响。此外，我们还研究了慢性间歇性低氧（CIH）这一具有性别特异性影响的氧化应激源是否会调节这些脑区中的 AR45 和 G 表达。
成年雄性和雌性 Sprague-Dawley 大鼠在睡眠期间接受 CIH 或常氧（室内空气）暴露 14 天。通过 Western blot 定量分析与各种认知相关的脑区[背侧海马 CA1、CA3、齿状回（DG）和内嗅皮层（ETC）]中的 AR45 和 G 蛋白表达。为了进行比较，还评估了海马-ETC 回路外的脑区[丘脑（TH）和纹状体（STR）]中的 AR45 和 G 蛋白表达。
AR45 水平最高的表达于海马 CA1 和 DG，而最低的表达见于外海马 STR。G 水平最高的表达于海马相关的 ETC，而最低的表达见于外海马的 TH。与雄性相比，雌性在海马 DG 中表达更高水平的 AR45，而无论在何种脑区评估，G 的表达均无性别差异。此外，CIH 对任何检查的脑区中的 AR45 或 G 表达均无影响。AR45 的表达与 CA1、DG、ETC、TH 和 STR 中的 G 表达呈性别依赖性正相关。
我们的研究结果表明，AR45 和 G 蛋白表达在海马-ETC 回路中富集，该回路在认知衰退期间易受氧化应激和神经退行性变的影响。然而，CIH 并不调节 AR45 或 G 的表达。重要的是，在各种脑区中，AR45 的表达及其与 G 表达的相关性存在性别差异，这可能是衰老过程中与认知和运动功能相关的下降存在性别差异的基础。
