BackgroundKnock-in (KI) mouse models of Alzheimer’s disease (AD) that endogenously overproduce Aβ without non-physiological overexpression of amyloid precursor protein (APP) provide important insights into the pathogenic mechanisms of AD. Previously, we reported that AppNL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited emotional alterations before the onset of definitive cognitive deficits. To determine whether these mice exhibit deficits in learning and memory at more advanced ages, we compared the Morris water maze performance of AppNL-G-F and AppNL mice, which harbor only the Swedish mutation, with that of wild-type (WT) C57BL/6J mice at the age of 24 months. To correlate cognitive deficits and neuroinflammation, we also examined Aβ plaque formation and reactive gliosis in these mice.ResultsIn the Morris water maze, a spatial task, 24-month-old AppNL-G-F/NL-G-F mice exhibited significantly poorer spatial learning than WT mice during the hidden training sessions, but similarly to WT mice during the visible training sessions. Not surprisingly, AppNL-G-F/NL-G-F mice also exhibited spatial memory deficits both 1 and 7 days after the last training session. By contrast, 24-month-old AppNL/NL mice had intact spatial learning and memory relative to WT mice. Immunohistochemical analyses revealed that 24-month-old AppNL-G-F/NL-G-F mice developed massive Aβ plaques and reactive gliosis (microgliosis and astrocytosis) throughout the brain, including the cortex and hippocampus. By contrast, we observed no detectable brain pathology in AppNL/NL mice despite overproduction of human Aβ40 and Aβ42 in their brains.ConclusionsAβ plaque formation, followed by sustained neuroinflammation, is necessary for the induction of definitive cognitive deficits in App-KI mouse models of AD. Our data also indicate that introduction of the Swedish mutation alone in endogenous APP is not sufficient to produce either AD-related brain pathology or cognitive deficits in mice.

中文翻译：

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β淀粉样蛋白斑块形成和反应性神经胶质增生是在阿尔茨海默病 App 敲入小鼠模型中诱导认知缺陷所必需的

背景阿尔茨海默病 (AD) 的基因敲入 (KI) 小鼠模型内源性过量产生 Aβ，而淀粉样前体蛋白 (APP) 非生理性过度表达，为了解 AD 的致病机制提供了重要的见解。此前，我们报道了携带三种家族性 AD 突变（瑞典突变、拜罗伊瑟/伊比利亚突变和北极突变）的 AppNL-GF 小鼠在出现明确的认知缺陷之前表现出情绪改变。为了确定这些小鼠在年龄较大时是否表现出学习和记忆缺陷，我们将仅携带瑞典突变的 AppNL-GF 和 AppNL 小鼠与野生型 (WT) C57BL/6J 小鼠的莫里斯水迷宫表现进行了比较24个月大的小鼠。为了将认知缺陷和神经炎症联系起来，我们还检查了这些小鼠的 Aβ 斑块形成​​和反应性神经胶质增生。结果在莫里斯水迷宫（一项空间任务）中，24 个月大的 AppNL-GF/NL-GF 小鼠表现出比 WT 小鼠明显更差的空间学习能力小鼠在隐藏训练期间，但与 WT 小鼠在可见训练期间类似。毫不奇怪，AppNL-GF/NL-GF 小鼠在最后一次训练后 1 天和 7 天也表现出空间记忆缺陷。相比之下，24 个月大的 AppNL/NL 小鼠相对于 WT 小鼠具有完整的空间学习和记忆能力。免疫组织化学分析显示，24 个月大的 AppNL-GF/NL-GF 小鼠在整个大脑（包括皮质和海马）中出现了大量 Aβ 斑块和反应性神经胶质增生（小胶质细胞增生和星形细胞增多）。相比之下，我们在 AppNL/NL 小鼠中没有观察到可检测到的大脑病理学，尽管它们的大脑中存在过量的人 Aβ40 和 Aβ42。 结论 Aβ 斑块形成​​以及随后的持续神经炎症对于在 App-KI 小鼠模型中诱导明确的认知缺陷是必要的。广告。我们的数据还表明，在内源性 APP 中单独引入瑞典突变不足以在小鼠中产生 AD 相关的大脑病理或认知缺陷。