Abstract
In preceding efforts, we demonstrated that antibiotic (ABX) cocktail-mediated perturbations of the gut microbiome in two independent transgenic lines, termed APPSWE/PS1ΔE9 and APPPS1-21, leads to a reduction in Aβ deposition in male mice. To determine whether these observed reductions of cerebral Aβ amyloidosis are specific to any individual antibiotic or require the synergistic effects of several antibiotics, we treated male APPPS1-21 transgenic mice with either individual ABX or an ABX cocktail and assessed amyloid deposition. Specifically, mice were subject to oral gavage with high dose kanamycin, gentamicin, colistin, metronidazole, vancomycin, individually or in a combination (ABX cocktail) from postnatal days (PND) 14 to 21, followed by ad libitum, low-dose individual ABX or ABX cocktail in the drinking water until the time of sacrifice. A control group was subject to gavage with water from PND 14 to 21 and received drinking water till the time of sacrifice. At the time of sacrifice, all groups showed distinct cecal microbiota profiles with the highest differences between control and ABX cocktail-treated animals. Surprisingly, only the ABX cocktail significantly reduced brain Aβ amyloidosis compared to vehicle-treated animals. In parallel studies, and to assess the potential exposure of ABX to the brain, we quantified the levels of each ABX in the brain by liquid chromatography-mass spectrometry (LC-MS) at PND 22 or at 7 weeks of age. With the exception of metronidazole (which was observed at less than 3% relative to the spiked control brains), we were unable to detect the other individual ABX in brain homogenates. Our findings suggest that synergistic alterations of gut microbial consortia, rather than individual antimicrobial agents, underlie the observed reductions in brain amyloidosis.
Highlights
Extracellular amyloid plaques composed of Aβ peptides and intraneuronal inclusions of tau in neurofibrillary tangles are the pathological hallmarks of Alzheimer’s disease[1,2]
We have shown that ABX-perturbed gut microbiome in two different transgenic mouse models of Aβ amyloidosis leads to a sex-specific reduction of brain amyloidosis in male mice[11,12]
To validate the use of our pseudo-germ-free mouse models of Aβ amyloidosis, we sought to address the following: (1) How do alterations in the gut microbiome in animals treated with individual ABX affect brain amyloidosis? and (2) do ABX affect brain amyloidosis by directly entering the brain and altering Aβ metabolism in a manner independent of alterations in the gut microbiota? To address the first issue, we investigated the impact of treating APPPS1-21 animals with individual antibiotics or the ABX cocktail in male mice only
Summary
Extracellular amyloid plaques composed of Aβ peptides and intraneuronal inclusions of tau in neurofibrillary tangles are the pathological hallmarks of Alzheimer’s disease[1,2]. We have shown that ABX-perturbed gut microbiome in two different transgenic mouse models of Aβ amyloidosis leads to a sex-specific reduction of brain amyloidosis in male mice[11,12]. To validate the use of our pseudo-germ-free mouse models of Aβ amyloidosis, we sought to address the following: (1) How do alterations in the gut microbiome in animals treated with individual ABX affect brain amyloidosis? To address the first issue, we investigated the impact of treating APPPS1-21 animals with individual antibiotics or the ABX cocktail in male mice only. The minimal brain exposure of metronidazole had no impact on levels of amyloid deposition These findings lead us to suggest that by mechanism(s) presently uncertain, alterations in microbial composition, but not brain exposure of each antibiotic are responsible for the observed reductions in Aβ amyloidosis in our mouse model
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