Stress confers risk for the development and progression of Alzheimer's disease (AD). Relative to men, women are disproportionately more likely to be diagnosed with this neurodegenerative disease. We hypothesized that sex differences in endocrine stress responsiveness may be a factor in this statistic. To test this hypothesis, we assessed basal and stress-induced corticosterone, social recognition, and coat state deterioration (surrogate for depression-like behavior) in male and female 3xTg-AD mice. Prior to reported amyloid plaque deposition, 3xTg females (4 months), but not 3xTg males, had heightened corticosterone responses to restraint exposure. Subsequently, only 3xTg females (6 months) displayed deficits in social memory concomitant with prominent β-amyloid (Aβ) immunostaining. These data suggest that elevated corticosterone stress responses may precede cognitive impairments in genetically vulnerable females. 3xTg mice of both sexes exhibited coat state deterioration relative to same-sex controls. Corticolimbic glucocorticoid receptor (GR) dysfunction is associated with glucocorticoid hypersecretion and cognitive impairment. Our findings indicate sex- and brain-region specific effects of genotype on hippocampal and amygdala GR protein expression. Because olfactory deficits may impede social recognition, in Experiment 2, we assessed olfaction and found no differences between genotypes. Notably, in this cohort, heightened corticosterone stress responses in 3xTg females was not accompanied by social memory deficits or coat state deterioration. However, coat state deterioration was consistent in 3xTg males. We report consistent heightened stress-induced corticosterone levels and Aβ pathology in female 3xTg-AD mice. However, the behavioral findings illuminate unknown inconsistencies in certain phenotypes in this AD mouse model.

压力会增加患阿尔茨海默氏病（AD）的风险。相对于男性，女性被诊断出患有这种神经退行性疾病的比例更高。我们假设内分泌应激反应的性别差异可能是该统计数据中的一个因素。为了检验该假设，我们评估了雄性和雌性3xTg-AD小鼠的基础和应激诱导的皮质酮，社会认可度以及皮层状态恶化（类似抑郁症行为的替代物）。在报道淀粉样斑块沉积之前，雌性3xTg（4个月），但雄性3xTg没有，对约束暴露的皮质酮反应增强。随后，只有3xTg的女性（6个月）显示出社交记忆缺陷，并伴有明显的β-淀粉样蛋白（Aβ）免疫染色。这些数据表明，在遗传上脆弱的女性中，皮质酮应激反应升高可能早于认知障碍。相对于同性对照，两个性别的3xTg小鼠均表现出被毛状态恶化。糖皮质激素性糖皮质激素受体（GR）功能障碍与糖皮质激素分泌过多和认知障碍有关。我们的发现表明基因型对海马和杏仁核GR蛋白表达的性别和脑区域特定影响。由于嗅觉缺陷可能会阻碍社会认可，因此在实验2中，我们评估了嗅觉，发现基因型之间没有差异。值得注意的是，在该队列中，3xTg女性中皮质酮应激反应的增强并未伴随社交记忆力不足或外衣状态恶化。但是，在3xTg的男性中，皮毛状态恶化是一致的。我们报告一致增强的雌性3xTg-AD小鼠应激诱导的皮质酮水平和Aβ病理。但是，该行为的发现说明了该AD小鼠模型中某些表型的未知不一致之处。