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Stools from a human APOEe2 donor reduces amyloid and tau pathology and increases neuroinflammation in a 3xTg AD mouse
Moira Marizzoni1, Benjamin B Tournier2,3, Claire Chevalier4
1Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Background:
The mechanisms underlying the protective effect of the e2 variant of the APOE gene (APOEe2) against Alzheimer's disease (AD) have not been elucidated. We altered the microbiota of 3xTgAD mice by fecal microbiota transplantation from a human APOEe2 donor (e2-FMT) and tested the effect of microbiota perturbations on brain AD pathology.
Methods:
FMT of bacteria isolated from stools of untreated 3xTgAD mice (M-FMT) or e2-FMT were transplanted in 15-month-old 3xTgAD mice. FMT was done alone or in combination with antibiotic and proton-pump inhibitor following the Microbiota Transfer Therapy protocol (MTT). The effect of donor (M or e2) and transplantation protocol (FMT or MTT) on hippocampal amyloid, tau pathology and neuroinflammation were assessed at the end of the treatment.
Results:
e2-FMT reduced amyloid, and tau pathology as well as increased neuroinflammation as compared with M-FMT. MTT was associated with reduced number of Aβ40+ plaques and tau pathology. Low levels of amyloid were associated with high levels of pro-inflammatory molecules in e2-FMT mice. These associations were partially attenuated by MTT.
Conclusion:
Bacteria from a human APOEe2 donor reduced AD pathology and increased neuroinflammation in mice suggesting that the gut microbiota may be a mediator of the protective effect of APOEe2.
Insights
Fecal microbiota transplantation from an APOEe2 donor reduced Alzheimer's disease pathology in mice. This suggests gut bacteria may mediate the protective effects of APOEe2 against AD.
Area of Science:
- Neuroscience
- Genetics
- Microbiology
Background:
- The protective mechanisms of the APOEe2 gene variant against Alzheimer's disease (AD) remain unclear.
- Investigating the role of gut microbiota in APOEe2's protective effects against AD.
Purpose of the Study:
- To determine if fecal microbiota transplantation (FMT) from an APOEe2 donor can alter Alzheimer's disease pathology in mice.
- To assess the impact of different transplantation protocols (FMT vs. Microbiota Transfer Therapy) on AD pathology.
Main Methods:
- 3xTgAD mice underwent fecal microbiota transplantation (FMT) from either a standard 3xTgAD mouse donor (M-FMT) or an APOEe2 human donor (e2-FMT).
- Some mice received FMT combined with antibiotics and a proton-pump inhibitor (Microbiota Transfer Therapy - MTT).
- Amyloid and tau pathology, along with neuroinflammation, were assessed in the hippocampus.
Main Results:
- e2-FMT significantly reduced amyloid and tau pathology compared to M-FMT.
- The Microbiota Transfer Therapy (MTT) protocol was associated with fewer amyloid plaques and reduced tau pathology.
- In e2-FMT mice, lower amyloid levels correlated with higher pro-inflammatory molecules, an effect partially reduced by MTT.
Conclusions:
- Gut bacteria from an APOEe2 donor can mitigate Alzheimer's disease pathology in a mouse model.
- Increased neuroinflammation was observed alongside reduced AD pathology, suggesting a complex interplay.
- Gut microbiota may act as a key mediator for the protective effects conferred by the APOEe2 gene variant.
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