Tu192 - Alzheimer’s Disease-derived Bacteroides Dorei Contributes to Cognitive Decline in a Strain-specific Manner

Abstract Text: The gut microbiota undergoes changes with aging and in Alzheimer's disease (AD), potentially contributing to cognitive decline by modulating immunity. We previously found that Bacteroides fragilis exacerbates amyloid-beta (A) plaque deposition by impairing microglial A phagocytosis. Given the functional diversity of bacteria, we explored how different Bacteroides species, depending on strain, might influence A uptake by myeloid cells.

We isolated Bacteroides dorei from AD and healthy control (HC) subjects and tested its effects on A uptake by RAW macrophages. We found that the HC-derived strain of B. dorei stimulated more A uptake than the AD-derived strain. To investigate in vivo effects, we administered live HC- or AD-derived B. dorei to APP/PS1 and wild-type (WT) mice from 4 to 7 months of age. Cognitive deficits were observed in female mice receiving AD-derived B. dorei, which impaired spatial memory. This strain also triggered higher levels of pro-inflammatory cytokines TNF-and IFN-, while HC-derived B. dorei reduced Grzb and IL-17 levels.

Additionally, bulk RNA sequencing of microglia revealed that AD-derived B. dorei increased metabolic processing pathways compared to HC-derived B. dorei.

These results suggest that B. dorei may have strain- and sex-specific effects on cognition in AD, possibly through an inflammatory response impacting microglia. Understanding the immunologic, metabolomic, and bacterial genomic differences between strains will provide novel insights into how the microbiome contributes to AD pathogenesis.