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Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimer's disease (AD) progression. However, the mechanisms of microbiome-brain interaction in AD, including the microbial mediators and their cellular targets in the brain, were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as key metabolites along the gut-brain axis in AD. Germ-free (GF) AD mice exhibit a substantially reduced Aβ plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice was sufficient to increase the Aβ plaque load to levels of conventionally colonized animals. While Aβ generation was only mildly affected, we observed strong microglial activation and upregulation of ApoE upon the SCFA supplementation. Taken together, our results demonstrate that microbiota-derived SCFA are the key mediators along the gut-brain axis resulting in increased microglial activation, ApoE upregulation and Aβ deposition. ### Competing Interest Statement The authors have declared no competing interest.

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