BCG vaccination mitigates tau pathology and restores cognitive function in PS19 mice
12 affiliations
- 1Center for Tuberculosis Research, Division of Infectious Diseases, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
- 2Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- 3Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- 4Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- 5Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University, Baltimore, MD, USA.
- 6F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, USA.
- 7Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
- 8Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- 9Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- 10Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- 11Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- 12Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Abstract
Retrospective studies in patients with nonmuscle invasive bladder cancer have reported a significant reduction in Alzheimer's disease incidence (12 to 78%) among Bacille Calmette-Guérin (BCG) recipients versus controls. To investigate the underlying mechanisms, we evaluated BCG in the PS19 mouse model of tauopathy. We found that BCG administration reduced hippocampal phospho-tau and microgliosis while preserving neuronal markers. In vivo volumetric T2-magnetic resonance Imaging (MRI) demonstrated attenuation of brain atrophy accompanied by increased glutamate-weighted chemical exchange saturation transfer-MRI signals. Functionally, BCG-treated mice showed improved performance in the novel object recognition test, as well as improved body-weight maintenance and survival. Transcriptomic profiling of the hippocampus revealed near complete normalization of the PS19 disease-associated gene expression signature toward that of healthy controls. Flow cytometric profiling of brain myeloid populations demonstrated a reduction in activated resident microglia, but total microglia cells remain elevated. Moreover, an increase of trained immunity marker CD80 on the recruited peripheral myeloid cells ensues following BCG treatment. Consistent with this shift in myeloid state, primary brain myeloid cells from BCG-treated mice also exhibited enhanced phagocytosis of fluorescein isothiocyanate-labeled tau fibrils and increased lactate production. Together, these findings indicate that BCG induces systemic and central nervous system myeloid cell reprogramming that limits neuroinflammation, enhances tau clearance, and rescues cognitive and neurodegenerative phenotypes in a tauopathy model. BCG is a safe, readily available therapy that merits consideration as a preventive agent against dementia.
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BibTeX
@article{shee2026vaccination,
title = {{BCG vaccination mitigates tau pathology and restores cognitive function in PS19 mice}},
author = {Somnath Shee and Meixiang Huang and Meghraj Singh Baghel and Yuxin Zheng and Shichun Lun and Santosh K. Yadav and Nirbhay N. Yadav and Carlos E. Ruiz-Gonzalez and Sandeep Tyagi and Eric Nuermberger and Sanjay K. Jain and Zaver M. Bhujwalla and Barbara S. Slusher and Philip C. Wong and William Bishai},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aej4603},
url = {https://www.science.org/doi/10.1126/sciadv.aej4603},
note = {CC BY},
}
RIS
TY - JOUR
TI - BCG vaccination mitigates tau pathology and restores cognitive function in PS19 mice
AU - Somnath Shee
AU - Meixiang Huang
AU - Meghraj Singh Baghel
AU - Yuxin Zheng
AU - Shichun Lun
AU - Santosh K. Yadav
AU - Nirbhay N. Yadav
AU - Carlos E. Ruiz-Gonzalez
AU - Sandeep Tyagi
AU - Eric Nuermberger
AU - Sanjay K. Jain
AU - Zaver M. Bhujwalla
AU - Barbara S. Slusher
AU - Philip C. Wong
AU - William Bishai
PY - 2026
DA - 2026/10/21
JO - Science Advances
DO - 10.1126/sciadv.aej4603
UR - https://www.science.org/doi/10.1126/sciadv.aej4603
AB - Retrospective studies in patients with nonmuscle invasive bladder cancer have reported a significant reduction in Alzheimer's disease incidence (12 to 78%) among Bacille Calmette-Guérin (BCG) recipients versus controls. To investigate the underlying mechanisms, we evaluated BCG in the PS19 mouse model of tauopathy. We found that BCG administration reduced hippocampal phospho-tau and microgliosis while preserving neuronal markers. In vivo volumetric T2-magnetic resonance Imaging (MRI) demonstrated attenuation of brain atrophy accompanied by increased glutamate-weighted chemical exchange saturation transfer-MRI signals. Functionally, BCG-treated mice showed improved performance in the novel object recognition test, as well as improved body-weight maintenance and survival. Transcriptomic profiling of the hippocampus revealed near complete normalization of the PS19 disease-associated gene expression signature toward that of healthy controls. Flow cytometric profiling of brain myeloid populations demonstrated a reduction in activated resident microglia, but total microglia cells remain elevated. Moreover, an increase of trained immunity marker CD80 on the recruited peripheral myeloid cells ensues following BCG treatment. Consistent with this shift in myeloid state, primary brain myeloid cells from BCG-treated mice also exhibited enhanced phagocytosis of fluorescein isothiocyanate-labeled tau fibrils and increased lactate production. Together, these findings indicate that BCG induces systemic and central nervous system myeloid cell reprogramming that limits neuroinflammation, enhances tau clearance, and rescues cognitive and neurodegenerative phenotypes in a tauopathy model. BCG is a safe, readily available therapy that merits consideration as a preventive agent against dementia.
SN - 2375-2548
ER -