Aquaporin-4 (AQP4) has been suggested to be involved in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD), which may be due to the modulation of neuroinflammation or the impairment of interstitial fluid bulk flow system in the central nervous system. Here, we show an age-dependent impairment of several behavioral outcomes in 5xFAD AQP4 null mice. Twenty-four-hour video recordings and computational analyses of their movement revealed that the nighttime motion of AQP4-deficient 5xFAD mice was progressively reduced between 20 and 36 weeks of age, with a sharp deterioration occurring between 30 and 32 weeks. This reduction in nighttime motion was accompanied by motor dysfunction and epileptiform neuronal activities, demonstrated by increased abnormal spikes by electroencephalography. In addition, all AQP4-deficient 5xFAD mice exhibited convulsions at least once during the period of the analysis. Interestingly, despite such obvious phenotypes, parenchymal amyloid β (Aβ) deposition, reactive astrocytosis, and activated microgliosis surrounding amyloid plaques were unchanged in the AQP4-deficient 5xFAD mice relative to 5xFAD mice. Taken together, our data indicate that AQP4 deficiency greatly accelerates an age-dependent deterioration of neuronal function in 5xFAD mice associated with epileptiform neuronal activity without significantly altering Aβ deposition or neuroinflammation in this mouse model. We therefore propose that there exists another pathophysiological phase in AD which follows amyloid plaque deposition and neuroinflammation and is sensitive to AQP4 deficiency.

中文翻译：

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在5xFAD转基因小鼠模型中Aquaporin-4的神经保护作用的行为和电生理证据。

已建议水通道蛋白4（AQP4）参与包括阿兹海默氏病（AD）在内的神经退行性疾病的发病机理，这可能是由于神经炎症的调节或中枢神经系统中的间质液大流量系统受损所致。在这里，我们显示了5xFAD AQP4无效小鼠的几种行为结果的年龄依赖性损伤。24小时的视频记录和对其运动的计算分析表明，缺乏AQP4的5xFAD小鼠的夜间运动在20至36周龄之间逐渐降低，在30至32周之间急剧恶化。夜间运动的减少伴有运动功能障碍和癫痫样神经元活动，这通过脑电图异常峰的增加得以证实。此外，在分析期间，所有AQP4缺陷型5xFAD小鼠至少出现一次惊厥。有趣的是，尽管有这种明显的表型，但相对于5xFAD小鼠，在缺乏AQP4的5xFAD小鼠中，实质性淀粉样β（Aβ）沉积，反应性星形细胞增多和淀粉样斑块周围的活化小胶质细胞增生没有改变。两者合计，我们的数据表明AQP4缺乏症大大加速了与癫痫状神经元活动相关的5xFAD小鼠的年龄依赖性神经元功能退化，而没有显着改变此小鼠模型中的Aβ沉积或神经炎症。因此，我们提出在AD中存在另一个病理生理学阶段，其遵循淀粉样斑块沉积和神经炎症并且对AQP4缺乏敏感。