Abstract
Recent evidence suggests the commensal microbiome regulates host immunity and influences brain function; findings that have ramifications for neurodegenerative diseases. In the context of Alzheimer’s disease (AD), we previously reported that perturbations in microbial diversity induced by life-long combinatorial antibiotic (ABX) selection pressure in the APPSWE/PS1ΔE9 mouse model of amyloidosis is commensurate with reductions in amyloid-β (Aβ) plaque pathology and plaque-localised gliosis. Considering microbiota-host interactions, specifically during early post-natal development, are critical for immune- and neuro-development we now examine the impact of microbial community perturbations induced by acute ABX exposure exclusively during this period in APPSWE/PS1ΔE9 mice. We show that early post-natal (P) ABX treatment (P14-P21) results in long-term alterations of gut microbial genera (predominantly Lachnospiraceae and S24-7) and reduction in brain Aβ deposition in aged APPSWE/PS1ΔE9 mice. These mice exhibit elevated levels of blood- and brain-resident Foxp3+ T-regulatory cells and display an alteration in the inflammatory milieu of the serum and cerebrospinal fluid. Finally, we confirm that plaque-localised microglia and astrocytes are reduced in ABX-exposed mice. These findings suggest that ABX-induced microbial diversity perturbations during post-natal stages of development coincide with altered host immunity mechanisms and amyloidosis in a murine model of AD.
Highlights
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that is pathologically characterised by the extracellular deposition of amyloid-β (Aβ) peptides in senile plaques and the intracellular accumulation of hyper-phosphorylated forms of tau protein in neurofibrillary tangles
We previously reported that ABX supplementation throughout the lifespan of aged APPSWE/PS1ΔE9 mice leads to altered gut microbial diversity, attenuation of Aβ plaque deposition in the brain and alterations in levels of cytokines and chemokines associated with innate immunity[35]
To address if microbial diversity during this post-natal development window impacts on amyloidosis in later life, we investigated if daily gavage with high-dose ABX only during the peri-weaning period, from P14-P21, might recapitulate the phenotypes observed previously in APPSWE/PS1ΔE9 mice subjected to life-long ABX exposure[35]
Summary
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that is pathologically characterised by the extracellular deposition of amyloid-β (Aβ) peptides in senile plaques and the intracellular accumulation of hyper-phosphorylated forms of tau protein in neurofibrillary tangles. While previous research investigating T-regulatory cell (T-reg) activity in facets of CNS repair remains conflicting[14,15,16,17], numerous studies suggest a beneficial, albeit complex, role of T-reg function in mitigating AD-like disease pathology In this regard, IL-2-mediated activation of the proliferative capacity of Foxp3+ T-regs alleviates cognitive deficits in the Thy1-APPSWE/PS1L166P mouse model of Aβ amyloidosis[18] and adoptive transfer of these cells improves spatial and temporal learning and reduces cortical and hippocampal Aβ plaque deposition in 3xTg familial AD (FAD) mice[19]. Supplementation of GF mice with SCFAs reverts these alterations to exhibit microglial phenotypes akin to specific pathogen free (SPF)-housed mice[29] and highlights the importance of not just the microbiota themselves, but their metabolic products, in regulating facets of brain function
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