Journal Article

DZNE-2021-00406

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition

Colombo, A. V. (First author)DZNE* ; Sadler, R. K. ; Llovera, G. ; Singh, V. ; Roth, S. ; Heindl, S. ; Sebastian Monasor, L.DZNE* ; Verhoeven, A. ; Peters, F.DZNE* ; Parhizkar, S. ; Kamp, F. ; Gomez de Aguero, M. ; MacPherson, A. J. ; Winkler, E.DZNE* ; Herms, J.DZNE* ; Benakis, C. ; Dichgans, M. ; Steiner, H.DZNE* ; Giera, M. ; Haass, C.DZNE* ; Tahirovic, S. (Corresponding author)DZNE* ; Liesz, A. (Corresponding author)

2021
eLife Sciences Publications Cambridge

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Please use a persistent id in citations: doi:10.7554/eLife.59826

Abstract: 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 were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as microbial metabolites which promote Aβ deposition. 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 increased the Aβ plaque load to levels of conventionally colonized (specific pathogen-free [SPF]) animals and SCFA supplementation to SPF mice even further exacerbated plaque load. This was accompanied by the pronounced alterations in microglial transcriptomic profile, including upregulation of ApoE. Despite increased microglial recruitment to Aβ plaques upon SCFA supplementation, microglia contained less intracellular Aβ. Taken together, our results demonstrate that microbiota-derived SCFA are critical mediators along the gut-brain axis which promote Aβ deposition likely via modulation of the microglial phenotype.

Keyword(s): Alzheimer Disease: metabolism (MeSH) ; Animals (MeSH) ; Fatty Acids, Volatile: metabolism (MeSH) ; Female (MeSH) ; Gastrointestinal Microbiome (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Microglia: metabolism (MeSH) ; Plaque, Amyloid: metabolism (MeSH) ; Specific Pathogen-Free Organisms (MeSH)

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Contributing Institute(s):

1. Juvenile Neurodegeneration (AG Tahirovic)
2. Biochemistry of γ-Secretase (AG Steiner)
3. Translational Brain Research (AG Herms)
4. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2021

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