Kertser, A. | bioRxiv Science

bioRxiv2025

Systemic administration of PD-L1 blocking antibodies leads to removal of senescent microglia

Senescent microglia develop during aging and Alzheimers disease (AD), driving chronic neuroinflammation. Here we hypothesized that the previously observed disease-modifying effects of PD-1/PD-L1 blockade occur through clearance of senescent microglia. Using CyTOF, we found that a single systemic anti-PD-L1 injection leads to rapid elimination of senescent microglia in 5xFAD and aged wild-type mice, independently of Fc effector function, while increasing homeostatic microglia. These findings suggest that immune rejuvenation via PD-L1 blockade promotes disease modification in AD through senescent-microglial elimination.

neuroscience↗

bioRxiv2025

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.

immunology↗