PD‐L1 blockade therapeutic effect in Tau P301S (line PS19) mouse model of tauopathy

Background There is a growing understanding that Alzheimer’s disease (AD) and tauopathies are not merely brain‐centric conditions, but encompass also dysfunction of the peripheral immune system that impacts disease onset and progression. We have previously shown, in several mouse models of AD, that blockade of the PD‐1/PD‐L1 immune checkpoint pathway facilitates homing of specialized immune cells to the brain, where these cells mitigate different pathomechanisms, ultimately leading to function improvement. Here, we tested PD‐L1 blockade in the Tau P301S (line PS19) mouse model of tauopathy. Methods Tau P301S mice were treated with anti‐PD‐L1 antibody, or isotype control, and tested for the functional effect of the treatment on parameters of cognitive performance and brain pathology, at different time points after treatment. Pharmacokinetic and pharmacodynamic events following treatment were evaluated to monitor the peripheral and central immune response. Treatment effects were also evaluated in TREM2 knockout Tau P301S mice. Results Dose‐dependent effect of anti‐PD‐L1 treatment was detected at 14‐ and 28‐days post‐treatment, with respect to cognitive performance of PS19 mice, as measured by T maze task. At the different timepoints following treatment we found reduction in cerebrospinal fluid total tau protein levels, and reduction in cortical phosphorylated tau (Ser404) protein levels. The functional effect on improvement of cognitive performance following anti‐PD‐L1 administration was also observed in TREM2 knockout Tau P301S mice, suggesting that the therapeutic effect of anti‐PD‐L1, is independent of TREM2 expression. Conclusions PD‐L1 blockade evokes an immune response that leads to functional improvement on cognitive performance and reduced brain pathology in Tau P301S mice. These findings, taken together with our previous reports of anti‐PD‐L1 therapeutic effect in other AD or tauopathy mouse models, substantiate the generalization of this treatment approach ‐ targeting the peripheral immune system in order to drive brain tissue repair in neurodegenerative conditions.