September 29, 2021

Bacteroides in the gut impair the clearance of amyloid-β in Alzheimer’s disease.

Caroline Wasen, PhD

Additional Authors: Laura M. Cox, Julia Vincentini, Juliana R. Lopes, Eduardo L.C. Lobo, Madelynn O’Brien, Howard L. Weiner

Introduction. Accumulation of amyloid-β (Aβ) peptides in the brain is an early feature of Alzheimer’s disease (AD). Microglia and monocytes aid in the clearance of Aβ and prevent the formation of amyloid plaques. However, this function declines in aging and in Alzheimer’s disease. We have identified species in the gut microbiota that are associated with Aβ levels in the brain of AD mice. Specifically, Bacteroides was associated with higher levels, and AD mice colonized with Bacteroides fragilis had more amyloid plaques (Cox et.al. 2019).

Method. APP/PS1 transgenic AD mice were treated with B. fragilis weekly starting at 2.5 months of age. The mice were sacrificed at 5 months of age, and the microglia transcriptional signature was analyzed. Aged wild-type C57BL/6J mice were treated with B. fragilis by weekly oral gavages. FITC-conjugated Aβ-42 (FITC-Aβ) peptides were injected into the hippocampus and Aβ uptake by microglia and monocytes was assessed by flow cytometry 14-18h later.

Results. In APP/PS1 mice, colonization of the gut with B. fragilis suppressed expression of 54 genes and increased expression of 10 genes related to protein homeostasis in microglia. Enriched KEGG pathways included lysosome, the phagosome, protein processing in the endoplasmic reticulum, autophagy, and FCgR-mediated phagocytosis. Among down regulated genes were Psen1, Itm2b, and Itm2c that participate in Aβ processing and aggregation, mutations in Psen1 that cause loss of function have been found in familial AD. In male WT mice treated with B. fragilis between 8-10 or 12-14 months of age (pooled) we observed a 2.4-fold reduction in FITC-Aβ uptake by monocytes (p=0.014), and a similar trend could be seen in microglia (1.7-fold reduction, p=0.097).

Conclusions. B. fragilis inhibited the uptake of Aβ, suppressed cellular pathways involved in the processing, aggregation and degradation of Aβ and may have a detrimental role in amyloid pathology.

References. Cox, L. M., et al. (2019). Scientific Reports 9(1): 17904.

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