Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer's disease-related signaling.
Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer's disease-related signaling.
复制标题
DOI：
10.1038/mp.2016.185
复制
发表时间：
2017-08
影响因子：
11
通讯作者：
Valentino RJ
中科院分区：
文献类型：
--
作者：
Bangasser DA;Dong H;Carroll J;Plona Z;Ding H;Rodriguez L;McKennan C;Csernansky JG;Seeholzer SH;Valentino RJ
几种神经精神和神经退行性疾病都将压力作为一个风险因素，并且在女性中比男性更普遍。促肾上腺皮质激素释放因子（CRF）协调应激反应，过量的CRF被认为有助于这些疾病的病理生理学。我们以前发现CRF 1受体（CRF 1）是性别偏见，从而耦合到其GTP结合蛋白，Gs，在女性中更大，而β-arrestin-2耦合在男性中更大。本研究使用磷酸化蛋白质组学方法在CRF过表达小鼠（CRF-OE）中测试原理证明，即当CRF过量时，性别偏倚的CRF 1偶联转化为不同的细胞信号传导，表达为不同的脑磷蛋白谱。区分雌性和雄性CRF-OE小鼠的皮质磷酸肽在独特的通路中过度表达，这与雌性中的GS依赖性信号传导和雄性中的β-抑制蛋白-2信号传导一致。值得注意的是，在雌性CRF-OE小鼠中更丰富的磷酸肽在阿尔茨海默病（AD）通路中过度表达。磷酸化蛋白质组学结果通过证明雌性CRF过表达与tau磷酸化增加相关，并且在AD病理学小鼠模型中，与β-分泌酶（参与淀粉样蛋白β形成的酶）磷酸化相关来验证。相对于雄性动物，这些雌性动物的β淀粉样蛋白斑块形成和认知障碍增加。总的来说，这些发现与一种机制是一致的，即作为压力相关疾病特征的过量CRF在男性和女性大脑中启动不同的细胞过程，这是性别偏见的CRF 1信号传导的结果。通过这种机制促进AD相关信号通路可能有助于女性对AD的易感性。
Several neuropsychiatric and neurodegenerative disorders share stress as a risk factor and are more prevalent in women than men. Corticotropin releasing factor (CRF) orchestrates the stress response and excessive CRF is thought to contribute to the pathophysiology of these diseases. We previously found that the CRF1 receptor (CRF1) is sex-biased whereby coupling to its GTP-binding protein, Gs, is greater in females, while β-arrestin-2 coupling is greater in males. This study used a phosphoproteomic approach in CRF-overexpressing mice (CRF-OE) to test the proof of principle that when CRF is in excess, sex-biased CRF1 coupling translates into divergent cell signaling that is expressed as different brain phosphoprotein profiles. Cortical phosphopeptides that distinguished female and male CRF-OE mice were overrepresented in unique pathways that were consistent with Gs-dependent signaling in females and β-arrestin-2 signaling in males. Notably, phosphopeptides that were more abundant in female CRF-OE mice were overrepresented in an Alzheimer's disease (AD) pathway. Phosphoproteomic results were validated by demonstrating that CRF overexpression in females was associated with increased tau phosphorylation and, in a mouse model of AD pathology, phosphorylation of β-secretase, the enzyme involved in formation of amyloid β. These females exhibited increased formation of amyloid β plaques and cognitive impairments relative to males. Collectively, the findings are consistent with a mechanism whereby the excess CRF that characterizes stress-related diseases initiates distinct cellular processes in male and female brains, as a result of sex biased CRF1 signaling. Promotion of AD-related signaling pathways through this mechanism may contribute to female vulnerability to AD.