Sex Differences in the Phosphoproteomic Profiles of APP/PS1 Mice after Chronic Unpredictable Mild Stress.
Sex Differences in the Phosphoproteomic Profiles of APP/PS1 Mice after Chronic Unpredictable Mild Stress.
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DOI：
10.3233/jad-191009
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发表时间：
2020
影响因子：
4
通讯作者：
Dong, Hongxin
中科院分区：
文献类型：
--
作者：
Dominguez, Sky;Rodriguez, Guadalupe;Fazelinia, Hossein;Ding, Hua;Spruce, Lynn;Seeholzer, Steven H.;Dong, Hongxin
大约三分之二的阿尔茨海默病（AD）患者是女性，然而，AD患病率性别差异的生物学机制仍然未知。先前的研究表明，性别特异性生化差异使雌性小鼠在促肾上腺皮质激素释放因子（CRF）过度表达后通过促肾上腺皮质激素释放因子（CRF）受体1激活而在磷酸蛋白质组水平上偏向于促AD信号传导。在这里，我们的目的是确定慢性应激是否会在AD小鼠模型中诱导类似的反应。我们强调4个月大的APP/PS1小鼠使用慢性不可预测的轻度应激（CIMIS）范式长达1个月。在进行行为学和行为学评估后，我们使用基于质谱的蛋白质组学定量了应激和非应激APP/PS1小鼠皮质中的全蛋白和磷蛋白水平。虽然在总蛋白质和肽丰度水平上没有统计学显著差异，但我们使用5%的错误发现率，分别在应激和未应激的女性和男性之间发现了909和841个统计学显著的磷酸肽。在这些显著的磷酸肽中，只有301个在雄性和雌性中相同。这些结果表明，虽然男性和女性都经历蛋白质磷酸化的变化后，压力，磷酸化的肽不同性别之间。然后，我们使用Metacore分析来确定哪些生物途径受到影响。我们发现雄性和雌性小鼠之间的几种途径发生了不同的变化，包括NMDA受体转运，细胞骨架组织和tau病理学。男性和女性在应对慢性压力时受到影响的不同生物学途径可能有助于我们更好地理解为什么女性患AD的风险更高。
Approximately two-thirds of those suffering with Alzheimer’s disease (AD) are women, however, the biological mechanisms underlying this sex divergence of AD prevalence remain unknown. Previous research has shown sex-specific biochemical differences that bias female mice toward pro-AD signaling on the phosphoproteomic level via corticotropin releasing factor (CRF) receptor 1 activation after CRF overexpression. Here we aimed to determine if chronic stress would induce a similar response in AD mouse models. We stressed 4-month-old APP/PS1 mice using a chronic unpredictable mild stress (CUMS) paradigm for up to 1 month. Following CUMS and behavioral assessments, we quantified whole protein and phosphoprotein levels in the cortex of stressed and non-stressed APP/PS1 mice using mass spectrometry-based proteomics. While there were no statistically significant differences at the total protein and peptide abundance levels, we found 909 and 841 statistically significant phosphopeptides between stressed and unstressed females and males, respectively, using a false discovery rate of 5%. Of these significant phosphopeptides, only 301 were the same in males and females. These results indicate that while both males and females undergo protein phosphorylation changes following stress, the peptides that are phosphorylated differ between sexes. We then used Metacore analysis to determine which biological pathways were affected. We found that several pathways were changed differently between male and female mice including NMDA receptor trafficking, cytoskeleton organization, and tau pathology. The differing biological pathways affected between males and females in response to chronic stress may help us to better understand why women are at a higher risk of AD.