Exacerbation of neurodegeneration by a metabolically engineered bacterium in a mouse model of tauopathy
- 1Washington University School of Medicine
Abstract
BackgroundTherapeutics that modulate peripheral and central immune responses are emerging as promising approaches for neurodegenerative disease. However, the biological context in which these interventions are deployed may critically influence therapeutic outcomes. An attenuated Brucella melitensis 16M strain and a similar strain engineered to express the metabolite indole have previously demonstrated therapeutic efficacy in preclinical models of cancer and autoimmunity through immune system modulation. Here, we tested whether repeated administration of these bacterial strains could modify pathological outcomes in a mouse model of tauopathy.
MethodsAttenuated Brucella strains were administered to transgenic mice overexpressing mutant tau protein on a human APOE4 knock-in background via intraperitoneal injection every 5 weeks starting at 6 months of age. Mice were analyzed at 9.5 months of age for tau pathology, neurodegeneration, and changes in innate and adaptive immune responses.
ResultsBrucella strains distributed predominantly in the periphery following repeated intraperitoneal treatment in transgenic mice, with minimal detection in the brain and no detection in the dural meninges. Repeated administration of either bacterial strain was well tolerated, with no evidence of adverse safety events. Surprisingly, repeated treatment with the engineered Brucella strain exacerbated neurodegenerative pathology, resulting in reduced hippocampal volume and increased phosphorylated tau pathology compared with control- and non-engineered Brucella strain -treated animals. Immunohistochemical analyses revealed increased numbers of hippocampal CD4+ T cells following treatment with either Brucella strain relative to PBS controls. However, only treatment with the engineered Brucella increased microglial reactivity within the hippocampus.
ConclusionThese findings demonstrate that peripheral administration of an engineered bacterial therapeutic can differentially influence neuroimmune responses and disease progression. These results underscore the importance of disease context when developing bacteria-based immunomodulatory therapies for neurodegenerative disorders.
Related
- In vivo positron emission tomography imaging of mitochondrial abnormalities in a mouse model of tauopathy
- Soluble pathogenic tau transmission to astrocytes drives acute oxidative damage, cellular senescence, and neurovascular uncoupling in a model of Alzheimers tauopathy
- A twentieth-century shift in psoriasis age at onset toward a metabolically associated phenotype
- Prevalence of NASH/NAFLD in people with obesity who are currently classified as metabolically healthy
- Alternatively polarized neutrophils metabolically restrain macrophage-driven inflammation
BibTeX
@misc{self2026exacerbation,
title = {{Exacerbation of neurodegeneration by a metabolically engineered bacterium in a mouse model of tauopathy}},
author = {W. K. Self and P. Sharma and G. Gent and M. E. Bosch and Y. Zhu and N. Powell and C. Agca and J. D. Ulrich and J. Song and P. de Figueiredo and D. M. Holtzman},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.755025},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.755025v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Exacerbation of neurodegeneration by a metabolically engineered bacterium in a mouse model of tauopathy
AU - W. K. Self
AU - P. Sharma
AU - G. Gent
AU - M. E. Bosch
AU - Y. Zhu
AU - N. Powell
AU - C. Agca
AU - J. D. Ulrich
AU - J. Song
AU - P. de Figueiredo
AU - D. M. Holtzman
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.755025
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.755025v1
AB - BackgroundTherapeutics that modulate peripheral and central immune responses are emerging as promising approaches for neurodegenerative disease. However, the biological context in which these interventions are deployed may critically influence therapeutic outcomes. An attenuated Brucella melitensis 16M strain and a similar strain engineered to express the metabolite indole have previously demonstrated therapeutic efficacy in preclinical models of cancer and autoimmunity through immune system modulation. Here, we tested whether repeated administration of these bacterial strains could modify pathological outcomes in a mouse model of tauopathy. MethodsAttenuated Brucella strains were administered to transgenic mice overexpressing mutant tau protein on a human APOE4 knock-in background via intraperitoneal injection every 5 weeks starting at 6 months of age. Mice were analyzed at 9.5 months of age for tau pathology, neurodegeneration, and changes in innate and adaptive immune responses. ResultsBrucella strains distributed predominantly in the periphery following repeated intraperitoneal treatment in transgenic mice, with minimal detection in the brain and no detection in the dural meninges. Repeated administration of either bacterial strain was well tolerated, with no evidence of adverse safety events. Surprisingly, repeated treatment with the engineered Brucella strain exacerbated neurodegenerative pathology, resulting in reduced hippocampal volume and increased phosphorylated tau pathology compared with control- and non-engineered Brucella strain -treated animals. Immunohistochemical analyses revealed increased numbers of hippocampal CD4+ T cells following treatment with either Brucella strain relative to PBS controls. However, only treatment with the engineered Brucella increased microglial reactivity within the hippocampus. ConclusionThese findings demonstrate that peripheral administration of an engineered bacterial therapeutic can differentially influence neuroimmune responses and disease progression. These results underscore the importance of disease context when developing bacteria-based immunomodulatory therapies for neurodegenerative disorders.
ER -