Shee, S.; Huang, M.; Baghel, M. S.; Zheng, Y.; Lun, S.; Yadav, S. K.; Yadav, N. N.; Ruiz-Gonzalez, C. E.; Tyagi, S.; Nuermberger, E.; Jain, S. K.; Bhujwalla, Z. M.; Slusher, B. S.; Wong, P. C.; Bishai, W.

Retrospective studies in patients with non-muscle invasive bladder cancer (NMIBC) have reported a significant reduction in Alzheimer's disease (AD) incidence (12-78%) among Bacillus Calmette-Guerin (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-MRI demonstrated attenuation of brain atrophy accompanied by increased glutamate-weighted CEST-MRI signals. Functionally, BCG-treated mice showed improved performance in the novel object recognition test (NORT), 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 towards 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 the co-stimulatory 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 FITC-labeled tau fibrils and increased lactate production. Together, these findings indicate that BCG induces systemic and CNS 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.