2023
We have demonstrated that in two mouse models of amyloid beta amyloidosis, male (but not female) mice treated with a cocktail of a broad spectrum of antibiotics (ABX) postnatally resulted in a dramatic reduction in amyloid beta plaques compared with mice treated with vehicle. Moreover, we have shown that ABX treatment results in alterations in the morphology and transcriptional state of microglia in proximity to plaques. More importantly, fecal matter transplants (FMT) from transgenic (or nontransgenic) mice into a cohort of ABX-treated male mice fully restores amyloid deposition and microglial signatures similar to vehicle-treated animals, thus arguing for causality of the fecal matter, including bacteria and/or fecal metabolites in pathogenesis. Our demonstration that amyloid beta plaque reduction following ABX treatment now has been reproduced in independent laboratories and multiple transgenic mouse models, but all the information we have gleaned with respect to amyloidosis and neuroinflammation was obtained at the time of cull. There is a paucity of spatiotemporal knowledge of amyloid beta plaque formation/reduction, microglial activation and changes of transcriptomic profiles in this transgenic mouse model following the perturbation of its gut microbiota. The surveillance of microglia cells is a persistent event, but the initial response of microglia cells to changes in the environment and the subsequent molecular alterations in microglia are not fully understood. Hence, we felt it was crucial to take snapshots of early events at various time points that occur in the brain of transgenic mice after ABX treatment. To this end, we are interested in monitoring, at a temporal level, ABX-mediated alterations in amyloid burden, microglial activation and the transcriptomic profile of microglial cells in mouse models.
Sangram S. Sisodia, Ph.D.
