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Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis and reactive microglia in a sex-specific manner.
Bosch, Megan E; Dodiya, Hemraj B; Michalkiewicz, Julia; Lee, Choonghee; Shaik, Shabana M; Weigle, Ian Q; Zhang, Can; Osborn, Jack; Nambiar, Aishwarya; Patel, Priyam; Parhizkar, Samira; Zhang, Xiaoqiong; Laury, Marie L; Mondal, Prasenjit; Gomm, Ashley; Schipma, Matthew John; Mallah, Dania; Butovsky, Oleg; Chang, Eugene B; Tanzi, Rudolph E; Gilbert, Jack A; Holtzman, David M; Sisodia, Sangram S.
Affiliation
  • Bosch ME; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, USA.
  • Dodiya HB; Department of Neurobiology, University of Chicago, Chicago, USA.
  • Michalkiewicz J; Department of Neurobiology, University of Chicago, Chicago, USA.
  • Lee C; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, USA.
  • Shaik SM; Department of Neurobiology, University of Chicago, Chicago, USA.
  • Weigle IQ; Department of Neurobiology, University of Chicago, Chicago, USA.
  • Zhang C; Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Osborn J; Department of Neurobiology, University of Chicago, Chicago, USA.
  • Nambiar A; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, USA.
  • Patel P; Center for Genetic Medicine, Northwestern University, Chicago, USA.
  • Parhizkar S; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, USA.
  • Zhang X; Department of Neurobiology, University of Chicago, Chicago, USA.
  • Laury ML; Genome Technology Access Center, Washington University in St. Louis, St. Louis, USA.
  • Mondal P; Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Gomm A; Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Schipma MJ; Center for Genetic Medicine, Northwestern University, Chicago, USA.
  • Mallah D; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Butovsky O; Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Chang EB; Department Medicine, Section of Gastroenterology, Hepatology, and Nutrition, The University of Chicago, Chicago, USA.
  • Tanzi RE; Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Gilbert JA; Department of Pediatrics and Scripps Institution of Oceanography, UCSD, San Diego, USA.
  • Holtzman DM; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, USA. holtzman@wustl.edu.
  • Sisodia SS; Department of Neurobiology, University of Chicago, Chicago, USA. ssisodia@bsd.uchicago.edu.
Mol Neurodegener ; 19(1): 18, 2024 Feb 17.
Article in En | MEDLINE | ID: mdl-38365827
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 Aß 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 Aß amyloidosis in the 5XFAD mouse model that were treated at a point when Aß 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, Aß 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 Aß burden was detectable upto 12 weeks of age when Aß 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 Aß burden was near peak levels. Subsequently, the two laboratories independently assessed amyloid-ß 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 Aß deposition or when given after Aß deposition is already at higher levels.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Alzheimer Disease / Gastrointestinal Microbiome / Amyloidosis Limits: Animals / Female / Humans / Male Language: En Journal: Mol Neurodegener Year: 2024 Document type: Article Affiliation country: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Alzheimer Disease / Gastrointestinal Microbiome / Amyloidosis Limits: Animals / Female / Humans / Male Language: En Journal: Mol Neurodegener Year: 2024 Document type: Article Affiliation country: United States