Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by a concerning rise in prevalence. It is projected that the number of affected individuals will reach a staggering 150 million by 2050. While recent advancements in monoclonal antibodies targeting Aβ have shown some clinical effects, there is an urgent need for improved therapies to effectively address the impeding surge of AD patients worldwide. To achieve this, a deeper understanding of the intricate mechanisms underlying the disease is crucial. In recent years, mounting evidence has underscored the vital role of the innate immune system in AD pathology. However, limited findings persist regarding the involvement of the adaptive immune system. Here, we report on the impact of the adaptive immune system on various aspects of AD by using App^NL-G-F mice crossed into a Rag2^−/− background lacking mature adaptive immune cells. In addition, to simulate the continuous exposure to various challenges such as infections that is commonly observed in humans, the innate immune system was activated through the repetitive induction of peripheral inflammation. We observed a remarkably improved performance on complex cognitive tasks when a mature adaptive immune system is absent. Notably, this observation is pathologically associated with lower Aβ plaque accumulation, reduced glial activation, and better-preserved neuronal networks in the mice lacking a mature adaptive immune system. Collectively, these findings highlight the detrimental role of the adaptive immune system in AD and underscore the need for effective strategies to modulate it for therapeutic purposes.

阿尔茨海默病（AD）是一种破坏性的神经退行性疾病，其患病率上升令人担忧。预计到 2050 年，受影响的人数将达到惊人的 1.5 亿。虽然针对 Aβ 的单克隆抗体的最新进展已显示出一些临床效果，但迫切需要改进的治疗方法，以有效解决全球 AD 患者激增的问题。为了实现这一目标，更深入地了解该疾病背后的复杂机制至关重要。近年来，越来越多的证据强调了先天免疫系统在 AD 病理学中的重要作用。然而，关于适应性免疫系统的参与，仍然存在有限的发现。在这里，我们通过使用App ^NL-GF小鼠与缺乏成熟适应性免疫细胞的 Rag2 ^−/−背景杂交，报告了适应性免疫系统对 AD 各个方面的影响。此外，为了模拟持续暴露于各种挑战，例如人类中常见的感染，通过重复诱导外周炎症来激活先天免疫系统。我们观察到，当成熟的适应性免疫系统不存在时，复杂认知任务的表现显着提高。值得注意的是，这一观察结果在病理学上与缺乏成熟适应性免疫系统的小鼠中 Aβ 斑块积累减少、神经胶质细胞活化减少以及神经元网络保存更好有关。总的来说，这些发现强调了适应性免疫系统在 AD 中的有害作用，并强调需要有效的策略来调节它以达到治疗目的。