Alzheimer’s disease (AD) is a neurodegenerative disease that causes memory and cognitive decline. Although many studies have attempted to clarify the causes of AD occurrence, it is not clearly understood. Recently, the emerging role of the gut microbiota in neurodegenerative diseases, including AD, has received much attention. The gut microbiota composition of AD patients and AD mouse models is different from that of healthy controls, and these changes may affect the brain environment. However, the specific mechanisms by which gut microbiota that influence memory decline are currently unclear. In this study, we performed fecal microbiota transplantation (FMT) to clarify the role of 5xFAD mouse-derived microbiota in memory decline. We observed that FMT from 5xFAD mice into normal C57BL/6 mice (5xFAD-FMT) decreased adult hippocampal neurogenesis and brain-derived neurotrophic factor expression and increased p21 expression, resulting in memory impairment. Microglia in the hippocampus of the 5xFAD-FMT mice were activated, which caused the elevation of pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1β). Moreover, we observed that pro-inflammatory cytokines increased in the colon and plasma of 5xFAD-FMT mice. The gut microbiota composition of the 5xFAD-FMT mice was different from that of the control mice or wild type-FMT mice. Collectively, 5xFAD mouse-derived microbiota decreased neurogenesis by increasing colonic inflammation, thereby contributing to memory loss. Our findings provide further evidence concerning the role of gut microbial dysbiosis in AD pathogenesis and suggest that targeting the gut microbiota may be a useful therapeutic strategy for the development of novel candidates for the treatment of AD.

阿尔茨海默病 (AD) 是一种神经退行性疾病，会导致记忆力和认知能力下降。尽管许多研究试图阐明 AD 发生的原因，但尚不清楚。最近，肠道微生物群在包括 AD 在内的神经退行性疾病中的新作用受到了广泛关注。AD患者和AD小鼠模型的肠道菌群组成与健康对照组不同，这些变化可能会影响大脑环境。然而，肠道微生物群影响记忆力下降的具体机制目前尚不清楚。在这项研究中，我们进行了粪便微生物群移植 (FMT) 以阐明 5xFAD 小鼠来源的微生物群在记忆力下降中的作用。我们观察到从 5xFAD 小鼠到正常 C57BL/6 小鼠 (5xFAD-FMT) 的 FMT 减少了成年海马神经发生和脑源性神经营养因子的表达，并增加了 p21 的表达，导致记忆障碍。5xFAD-FMT 小鼠海马中的小胶质细胞被激活，导致促炎细胞因子（肿瘤坏死因子-α 和白细胞介素-1β）升高。此外，我们观察到 5xFAD-FMT 小鼠的结肠和血浆中促炎细胞因子增加。5xFAD-FMT 小鼠的肠道菌群组成与对照小鼠或野生型 FMT 小鼠的肠道菌群组成不同。总的来说，5xFAD 小鼠来源的微生物群通过增加结肠炎症来减少神经发生，从而导致记忆丧失。