A single injection of anti-PD-L1 blocking antibody induces a transient reduction in tau pathology in P301S (PS19) mouse model of tauopathy

Blocking the inhibitory PD-1/PD-L1 immune checkpoint pathway has been shown to arrest cognitive decline and reduce multiple aspects of brain pathology in various mouse models of amyloidosis and tauopathy. In this study, we evaluated whether anti-PD-L1 treatment would be effective in a tauopathy model characterized by rapidly progressing pathology. Using the P301S (PS19) transgenic mouse model, we found that a single injection of anti-PD-L1 antibody significantly attenuated cognitive deficits, with effects detectable 1-month post-treatment, aligned with the kinetics reported in other models. This cognitive benefit was observed irrespective of microglial TREM2 signalling. The effect on brain pathology was transient; phosphorylated tau in the brain, and total tau in the cerebrospinal fluid were significantly reduced 14 days post-treatment but not at 28 days. These findings indicate that PD-L1 blockade is effective across multiple disease models, while emphasizing the importance of carefully monitoring the timing of effect assessments, treatment outcomes, and dosing frequency, especially in models with accelerated disease progression.