Vaccination with BCG reduces tau pathology and improve memory behaviors in the PS19 dementia mouse model

Retrospective studies among non-muscle invasive bladder cancer (NMIBC) patients have reported significant reductions (12–78%) in Alzheimer's disease (AD) incidence among BCG recipients versus controls. To understand the underlying mechanisms and discover novel therapeutic targets, we tested Mycobacterium bovis BCG Pasteur in a PS19 (P301S) mice model, which develop tauopathy-dependent neurodegeneration. We showed that BCG reduced hippocampal phospho‑tau, microgliosis, and astrocyte activation while preserving neuronal markers. In vivo T2-MRI showed mitigated atrophy, with simultaneously increasing glutamate‑weighted CEST‑MRI readouts. Additionally, BCG improved survival and body weight, and amended cognitive physiology. Bulk-RNA sequencing of the hippocampus revealed- (1) restoration of the transcriptomics landscape of PS19 mice towards non-carrier controls after BCG-therapy, and interestingly (2) augmented antigen processing coupled with reduced neuroinflammation. Brain myeloid cell profiling by multicolor flow cytometry revealed decreased CD45hi-activated microglia subpopulation, without increasing total microglia, alongside elevated CD80 (Trained immunity marker) on peripheral myeloid cells. Functionally, primary brain myeloid cells displayed greater uptake of FITC‑tau fibrils and higher lactate production, indicating enhanced phagocytosis and glycolytic metabolism. Together, these findings indicate that (1) BCG-driven myeloid reprogramming limits neuroinflammation, enhances tau clearance, and rescues cognitive defects in a tauopathy model, and (2) BCG therapy merit consideration for human clinical trials against AD.