Interleukin-12/23 deficiency differentially affects pathology in male and female Alzheimer's disease-like mice
Interleukin-12/23 deficiency differentially affects pathology in male and female Alzheimer's disease-like mice
复制标题
DOI：
10.15252/embr.201948530
复制
发表时间：
2020-01-30
期刊：
影响因子：
7.7
通讯作者：
Heppner, Frank L.
中科院分区：
文献类型：
--
作者：
Eede, Pascale;Obst, Juliane;Heppner, Frank L.
β 淀粉样蛋白 (Aβ) 的病理性聚集是阿尔茨海默病 (AD) 的主要标志。最近的遗传关联研究将先天免疫系统的作用与 AD 的发展联系起来，目前的证据表明 AD 发病机制中存在深刻的性别差异。在这里，我们描述了 APP23 AD 样小鼠模型中性别特异性的病理特征，发现雌性小鼠与雄性小鼠相比表现出更强的淀粉样变性和星形胶质细胞增生。我们测试了缺乏 IL12p40 的性别特异性效应，IL12p40 是白细胞介素 (IL)-12 和 IL-23 的共享亚基，我们之前曾报道过 IL12p40 可改善 APPPS1 小鼠的病理学。 IL12p40 缺陷性别特异性降低雄性 APP23 小鼠的 A β 斑块负担，而在雌性小鼠中，可溶性 A β(1-40) 显着减少，而 A β 斑块负担没有变化。同样，缺乏 IL12p40 的雌性和雄性 APP23 小鼠的血浆和脑细胞因子水平发生不同的变化，而神经胶质特性则没有变化。这些数据证实了针对 AD 中 IL-12/IL-23 信号传导的治疗潜力，但也强调了在研究免疫系统和 AD 的作用时考虑性别的重要性。
Pathological aggregation of amyloid-beta (A beta) is a main hallmark of Alzheimer's disease (AD). Recent genetic association studies have linked innate immune system actions to AD development, and current evidence suggests profound gender differences in AD pathogenesis. Here, we characterise gender-specific pathologies in the APP23 AD-like mouse model and find that female mice show stronger amyloidosis and astrogliosis compared with male mice. We tested the gender-specific effect of lack of IL12p40, the shared subunit of interleukin (IL)-12 and IL-23, that we previously reported to ameliorate pathology in APPPS1 mice. IL12p40 deficiency gender specifically reduces A beta plaque burden in male APP23 mice, while in female mice, a significant reduction in soluble A beta(1-40) without changes in A beta plaque burden is seen. Similarly, plasma and brain cytokine levels are altered differently in female versus male APP23 mice lacking IL12p40, while glial properties are unchanged. These data corroborate the therapeutic potential of targeting IL-12/IL-23 signalling in AD, but also highlight the importance of gender considerations when studying the role of the immune system and AD.