Marizzoni Moira, Tournier Benjamin B, Chevalier Claire, Saleri Samantha, Lathuilière Aurélien, Ceyzériat Kelly, Paquis Arthur, Park Rahel, Troesch Emma, Cattaneo Annamaria, Millet Philippe, Frisoni Giovanni B
Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland.
Front Aging Neurosci. 2025 Feb 14;17:1539067. doi: 10.3389/fnagi.2025.1539067. eCollection 2025.
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.
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.
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.
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.
载脂蛋白E基因的e2变体（APOEe2）对阿尔茨海默病（AD）具有保护作用，但其潜在机制尚未阐明。我们通过将人类APOEe2供体的粪便微生物群移植到3xTgAD小鼠体内来改变其微生物群，并测试微生物群扰动对脑AD病理的影响。
将从未经治疗的3xTgAD小鼠粪便中分离出的细菌进行粪便微生物群移植（M-FMT）或e2-FMT，移植到15月龄的3xTgAD小鼠体内。按照微生物群转移疗法方案（MTT）单独进行FMT或与抗生素和质子泵抑制剂联合进行。在治疗结束时评估供体（M或e2）和移植方案（FMT或MTT）对海马淀粉样蛋白、tau病理和神经炎症的影响。
与M-FMT相比，e2-FMT减少了淀粉样蛋白和tau病理，并增加了神经炎症。MTT与Aβ40+斑块数量减少和tau病理减轻有关。在e2-FMT小鼠中，低水平的淀粉样蛋白与高水平的促炎分子有关。MTT部分减弱了这些关联。
来自人类APOEe2供体的细菌减少了小鼠的AD病理并增加了神经炎症，这表明肠道微生物群可能是APOEe2保护作用的介导者。
