Pathological aggregation of amyloid-β (Aβ) 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 Aβ plaque burden in male APP23 mice, while in female mice, a significant reduction in soluble Aβ1-40 without changes in Aβ 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.

中文翻译：

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IL-12/23 缺乏对雄性和雌性阿尔茨海默病样小鼠的病理学有不同的影响。

β-淀粉样蛋白 (Aβ) 的病理聚集是阿尔茨海默病 (AD) 的主要标志。最近的遗传关联研究已将先天免疫系统作用与 AD 发展联系起来，目前的证据表明 AD 发病机制中存在巨大的性别差异。在这里，我们描述了 APP23 AD 样小鼠模型中的性别特异性病理，发现与雄性小鼠相比，雌性小鼠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 的性别特异性影响，IL12p40 是白细胞介素 (IL)-12 和 IL-23 的共享亚基，我们之前报道过它可以改善 APPPS1 小鼠的病理学。IL12p40 缺乏性别特异性降低雄性 APP23 小鼠的 Aβ 斑块负荷，而在雌性小鼠中，可溶性 Aβ1-40 显着减少，而 Aβ 斑块负荷没有变化。相似地，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了不同的变化，而神经胶质特性没有改变。这些数据证实了靶向 IL-12/IL-23 信号在 AD 中的治疗潜力，但也强调了在研究免疫系统和 AD 的作用时性别考虑的重要性。