Abstract
It has recently become well-established that there is a connection between Alzheimer’s disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by the finding that a marine-derived oligosaccharide, GV-971, was reported to alter gut microbiota and reduce Aβ amyloidosis in the 5XFAD mouse model that were treated at a point when Aβ burden was near plateau levels. Utilizing comparable methodologies, but with distinct technical and temporal features, we now report on the impact of GV-971 on gut microbiota, Aβ amyloidosis and microglial phenotypes in the APPPS1-21 model, studies performed at the University of Chicago, and independently in the 5X FAD model, studies performed at Washington University, St. Louis. Methods To comprehensively characterize the effects of GV-971 on the microbiota-microglia-amyloid axis, we conducted two separate investigations at independent institutions. There was no coordination of the experimental design or execution between the two laboratories. Indeed, the two laboratories were not aware of each other’s experiments until the studies were completed. Male and female APPPS1-21 mice were treated daily with 40, 80, or 160 mg/kg of GV-971 from 8, when Aβ burden was detectable upto 12 weeks of age when Aβ burden was near maximal levels. In parallel, and to corroborate existing published studies and further investigate sex-related differences, male and female 5XFAD mice were treated daily with 100 mg/kg of GV-971 from 7 to 9 months of age when Aβ burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-β deposition, metagenomic, and neuroinflammatory profiles. Finally, studies were initiated at the University of Chicago to evaluate the metabolites in cecal tissue from vehicle and GV-971-treated 5XFAD mice. Results These studies showed that independent of the procedural differences (dosage, timing and duration of treatment) between the two laboratories, cerebral amyloidosis was reduced primarily in male mice, independent of strain. We also observed sex-specific microbiota differences following GV-971 treatment. Interestingly, GV-971 significantly altered multiple overlapping bacterial species at both institutions. Moreover, we discovered that GV-971 significantly impacted microbiome metabolism, particularly by elevating amino acid production and influencing the tryptophan pathway. The metagenomics and metabolomics changes correspond with notable reductions in peripheral pro-inflammatory cytokine and chemokine profiles. Furthermore, GV-971 treatment dampened astrocyte and microglia activation, significantly decreasing plaque-associated reactive microglia while concurrently increasing homeostatic microglia only in male mice. Bulk RNAseq analysis unveiled sex-specific changes in cerebral cortex transcriptome profiles, but most importantly, the transcriptome changes in the GV-971-treated male group revealed the involvement of microglia and inflammatory responses. Conclusions In conclusion, these studies demonstrate the connection between the gut microbiome, neuroinflammation, and Alzheimer’s disease pathology while highlighting the potential therapeutic effect of GV-971. GV-971 targets the microbiota-microglia-amyloid axis, leading to the lowering of plaque pathology and neuroinflammatory signatures in a sex-dependent manner when given at the onset of Aβ deposition or when given after Aβ deposition is already at higher levels.
Original language | English (US) |
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Article number | 18 |
Journal | Molecular neurodegeneration |
Volume | 19 |
Issue number | 1 |
DOIs | |
State | Published - Dec 2024 |
Funding
We thank the Genome Technology Access Center at the McDonnell Genome Institute at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant# UL1TR002345 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. This work was supported, in part, by the Bursky Center for Human Immunology and Immunotherapy Programs at Washington University, Immunomonitoring Laboratory. The work at The University of Chicago was supported, in part, through a Sponsored Research Agreement from Shanghai Green Valley Pharmaceutical Co, Inc. We thank Ms. Shirley Bond and Dr. Christine Labno for slide scanner image processing at the University of Chicago Integrated Light Microscopy Core Facility. We thank Michael Nuenninghoff and Dr. Pieter W. Faber for their help with bioanalyzer and next-generation sequencing services at the University of Chicago Genomics Core Facility. We thank the University of Chicago Digestive Disease Research Core Center for their help with genomic analysis. The core is supported by NIDDK P30 DK042086. We thank Dr. Ashley M. Sidebottom and the Duchossois Family Institute Host-Microbe Metabolomics Facility team for the targeted metabolite mass spectrometry services and analyses. We thank Ms. Shirley Bond and Dr. Christine Labno for slide scanner image processing at the University of Chicago Integrated Light Microscopy Core Facility. We thank Michael Nuenninghoff and Dr. Pieter W. Faber for their help with bioanalyzer and next-generation sequencing services at the University of Chicago Genomics Core Facility. We thank the University of Chicago Digestive Disease Research Core Center for their help with genomic analysis. The core is supported by NIDDK P30 DK042086. We thank Dr. Ashley M. Sidebottom and the Duchossois Family Institute Host-Microbe Metabolomics Facility team for the targeted metabolite mass spectrometry services and analyses. We thank the Genome Technology Access Center at the McDonnell Genome Institute at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by NCI Cancer Center Support Grant #P30 CA91842 to the Siteman Cancer Center and by ICTS/CTSA Grant# UL1TR002345 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. This work was supported, in part, by the Bursky Center for Human Immunology and Immunotherapy Programs at Washington University, Immunomonitoring Laboratory. The work at The University of Chicago was supported, in part, through a Sponsored Research Agreement from Shanghai Green Valley Pharmaceutical Co, Inc. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH.
Keywords
- Alzheimer’s disease
- Microbiome
- Microglia
- Neuroinflammation
- Sodium oligomannate
ASJC Scopus subject areas
- Molecular Biology
- Clinical Neurology
- Cellular and Molecular Neuroscience