Gut microbiota regulates neuroinflammation and progression of neurodegeneration in a mouse model of tauopathy

Abstract

AbstractBackgroundAlthough mounting evidence supports that an unbalanced gut microbiota (GM) is linked to amyloid‐β deposition, the contribution of the GM to tau‐mediated neurodegeneration (TN) is poorly characterized. Our preliminary data have shown that the GM manipulations, using either treatment with a combination of antibiotics (ABX) or raising animals in germ‐free (GF) conditions, regulate TN (Seo, et al., AAIC 2021). However, further investigation is needed to sort out the underlying mechanisms that are involved in the interaction between GM and TN. Here, we explore neuroinflammation as a potential mediator in the interaction between GM and TN.MethodP301S 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. Each group was gavaged with either ABX or H2O from postnatal day 16‐22, housed in a specific pathogen‐free facility, and euthanized at 9.5 months of age. A separate group of TE4F mice was housed under GF conditions. Collected brains were sectioned and used for immunohistochemistry analysis.ResultsIn agreement with brain atrophy measurements that we previously reported, TE3F mice treated with a short‐term ABX showed significantly lower phosphorylated tau (p‐tau) staining compared to the H2O‐treated group (p < 0.01), but not TE4F and TEKO mice treated with ABX. GF‐TE4F mice also showed a marked decrease in p‐tau staining compared to conventionally‐raised animals (p < 0.01). Further quantification of gliosis, as measured by GFAP and Iba1 immunostaining, did not reveal any ABX treatment effects. However, when we assessed the expression of clec7a+ microglia, which marks reactive microglia, ABX treated animals showed significantly lower clec7a+ staining across the different APOE isoform groups (p < 0.01). Furthermore, microglial morphology analysis revealed that ABX treatment drive microglia to a more homeostatic‐like state in TE3F mice, but not in TE4F nor TEKO mice. Remarkably, GF‐TE4F mice showed a marked decrease in both GFAP and Iba1 expression compared to the control TE4F mice (p < 0.05).ConclusionOur results support the hypothesis that GM manipulation modulates tau‐mediated neurodegeneration via influencing a neuroinflammatory mechanism.