It was recently revealed that gut microbiota promote amyloid-beta (Aβ) burden in mouse models of Alzheimer’s disease (AD). However, the underlying mechanisms when using either germ-free (GF) housing conditions or treatments with antibiotics (ABX) remained unknown. In this study, we show that GF and ABX-treated 5x familial AD (5xFAD) mice developed attenuated hippocampal Aβ pathology and associated neuronal loss, and thereby delayed disease-related memory deficits. While Aβ production remained unaffected in both GF and ABX-treated 5xFAD mice, we noticed in GF 5xFAD mice enhanced microglial Aβ uptake at early stages of the disease compared to ABX-treated 5xFAD mice. Furthermore, RNA-sequencing of hippocampal microglia from SPF, GF and ABX-treated 5xFAD mice revealed distinct microbiota-dependent gene expression profiles associated with phagocytosis and altered microglial activation states. Taken together, we observed that constitutive or induced microbiota modulation in 5xFAD mice differentially controls microglial Aβ clearance mechanisms preventing neurodegeneration and cognitive deficits.

中文翻译：

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组成性和诱导性微生物群调节对阿尔茨海默氏病小鼠模型中小胶质细胞的不同影响。

最近发现，肠道菌群在阿尔茨海默氏病（AD）小鼠模型中促进淀粉样β（Aβ）负担。但是，使用无菌（GF）住房条件或使用抗生素（ABX）进行治疗时的潜在机制仍然未知。在这项研究中，我们表明GF和ABX处理的5x家族性AD（5xFAD）小鼠出现了海马Aβ病理学减弱和相关神经元丢失，从而延迟了与疾病相关的记忆缺陷。尽管在GF和ABX处理的5xFAD小鼠中Aβ的产生均不受影响，但我们注意到在GF 5xFAD小鼠中，与ABX处理的5xFAD小鼠相比，在疾病早期阶段小胶质Aβ的摄取增加。此外，来自SPF的海马小胶质细胞RNA测序 GF和ABX处理的5xFAD小鼠显示与吞噬作用和改变的小胶质细胞活化状态相关的独特的微生物群依赖性基因表达谱。综上所述，我们观察到5xFAD小鼠的组成型或诱导型微生物群调节差异控制小胶质Aβ清除机制，从而防止神经变性和认知缺陷。