Evidence that the gut microbiota regulates progression of neurodegeneration in a mouse model of tauopathy, in a sex‐ and ApoE isoform‐dependent manner

Alzheimer's disease (AD) is a fatal progressive neurodegenerative disease. Mounting evidence supports that an unbalanced gut microbiota (GM) is linked to amyloid-β deposition potentially by disrupting neuroinflammation and metabolic homeostasis. However, the contribution of the GM to tau-mediated neurodegeneration is poorly characterized. Furthermore, recent studies have reported that the configuration of the GM is also affected by ApoE isoforms, which is the strongest genetic risk factor for late-onset AD. Here, we explore the hypothesis that the GM regulates tau-mediated neurodegeneration in a sex- and ApoE isoform- dependent manner, using a mouse model of tauopathy.Male and female P301S tau transgenic mice were crossed with human ApoE knock-in mice (ApoE3 or ApoE4) or ApoE knockout mice (EKO) to generate P301S::ApoE3/E3, ApoE4/E4, or P301S/EKO mice, termed TE3F, TE4F, and TEKO, respectively. The GM in each group was perturbed by gastric gavage of a combination of antibiotics (ABX) from post-natal day 16-22; controls were gavaged with water (H2O). Mice were housed in a specific pathogen-free facility and fed a standard mouse chow diet ad libitum until they were euthanized at 9 months of age. In addition, a separate group of male and female TE4F mice were housed under germ-free conditions. Collected brains were sectioned, stained with 0.1% Sudan black and used to measure volumes of regions of interest.In males, TE3F and TE4F mice treated with H2O showed significant hippocampal atrophy compared to P301S mice lacking a functional ApoE gene (TEKO). However, TE3F mice treated with a short-term ABX showed significantly milder hippocampal atrophy compared to the water-treated group (p < 0.001, t-test). ABX treatment of TE4F animals was also associated with milder atrophy, although the effect did not reach statistical significance (p = 0.09, t-test). There were no effects in TEKO mice treated with ABX. Remarkably, these phenotypic effects of ABX treatment were not observed in females. Moreover, germ-free TE4F mice showed a marked decrease in brain atrophy compared to conventionally-raised animals; this was true for both sexes.Our results indicate that tau-mediated neurodegeneration occurs in a ApoE- dependent manner and is influenced by the gut microbiota and gender.