# Microbial Composition, Disease Trajectory and Genetic Background in a Slow Onset Model of Frontotemporal Lobar Degeneration

## TL;DR

This study explores how gut microbes and genetic background influence tau accumulation and disease progression in a mouse model of frontotemporal lobar degeneration.

## Contribution

The study reveals that gut microbial composition and genetic background affect tau neuropathology and survival in a transgenic mouse model of neurodegeneration.

## Key findings

- Gut microbial genotypes differ between C57BL6/Tac and 129SvEv/Tac TgTauP301L sublines and influence tau accumulation patterns.
- Cg C57BL6/Tac TgTauP301L mice showed a 28% intercurrent loss compared to 9% in 129SvEv/Tac mice (p = 0.0027).
- Environmental factors like fecal microbial transplantation altered tau neuropathology in aged mice.

## Abstract

Slow-onset neurodegenerative disease in a low-expresser 2N4R P301L transgenic (Tg) mouse model is marked by neuroinflammation and by differing patterns of CNS deposition and accumulation of tau conformers, with such heterogeneities present even within inbred backgrounds. Gut microbial genotypes were notably divergent within C57BL6/Tac or 129SvEv/Tac congenic (Cg) sublines of TgTauP301L mice, and these sublines differed when challenged with antibiotic treatment and fecal microbial transplantation. Whereas aged, transplanted Cg 129SvEv/Tac TgTauP301L mice had neuroanatomical deposition of tau resembling controls, transplanted Cg C57BL6/Tac TgTauP301L mice had different proportions of rostral versus caudal tau accumulation (p = 0.0001). These data indicate the potential for environmental influences on tau neuropathology in this model. Furthermore, Cg C57BL6/Tac TgTauP301L cohorts differed from 129SvEv/Tac counterparts by showing 28% versus 9% net intercurrent loss (p = 0.0027). While the origin of this phenomenon is not established, it offers a parallel to differing patterns of frailty observed in C57BL6 versus 129 SvEv Tg mice expressing the 695 amino acid isoform of human amyloid precursor protein. We infer that generalized responses to protein aggregation might account for similar reductions in viability even when expressing different human proteins in the same inbred strain background.