Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1ΔE9 murine model of Alzheimer's disease

Sci Rep. 2017 Sep 5;7(1):10411. doi: 10.1038/s41598-017-11047-w.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / etiology*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / metabolism
  • Amyloidosis / genetics*
  • Amyloidosis / metabolism
  • Amyloidosis / pathology
  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Biodiversity
  • Biomarkers
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal
  • Gastrointestinal Microbiome
  • Inflammation Mediators / metabolism
  • Male
  • Metagenome
  • Metagenomics / methods
  • Mice
  • Mice, Transgenic
  • Microbiota / drug effects*
  • Neuroimmunomodulation / drug effects
  • Neuroimmunomodulation / genetics
  • Neuroimmunomodulation / immunology
  • Plaque, Amyloid / etiology
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • RNA, Ribosomal, 16S / genetics

Substances

  • Amyloid beta-Protein Precursor
  • Anti-Bacterial Agents
  • Biomarkers
  • Inflammation Mediators
  • RNA, Ribosomal, 16S