Abstract
Programmed cell death protein 1 (PD-1) checkpoint blockade with an antibody has been shown to reduce amyloid-β plaques, associated pathologies and cognitive impairment in mouse models. More recently, this approach has shown effectiveness in a tauopathy mouse model to improve cognition and reduce tau lesions. Follow-up studies by other laboratories did not see similar benefits of this type of therapy in other amyloid-β plaque models. Here, we report a modest increase in locomotor activity but no effect on cognition or tau pathology, in a different more commonly used tauopathy model following a weekly treatment for 12 weeks with the same PD-1 antibody and isotype control as in the original Aβ- and tau-targeting studies. These findings indicate that further research is needed before clinical trials based on PD-1 checkpoint immune blockage are devised for tauopathies.
Highlights
Programmed death ligand 1 (PD-L1) binds to its receptor, programmed cell death protein 1 (PD-1), resulting in complex effects on the immune system (Chamoto et al, 2017; Wei et al, 2018)
Their brains were analyzed for tau and phospho-tau levels in soluble and sarkosyl insoluble fractions by Western blots and Enzyme-Linked Immunosorbent Assay (ELISA) to determine if the PD-1 treatment led to clearance of pathological tau protein
Sensorimotor Tests Locomotor Activity The PD-1 treatment group was more active in the open field compared to the IgG control group, traveling 23% further (p < 0.05; Figure 1A) and at a 23% greater speed {IgG: 3.59 ± 0.18 cm/s, PD-1: 4.43 ± 0.30 cm/s [average ± standard error of the mean (SEM)], p < 0.05}
Summary
Programmed death ligand 1 (PD-L1) binds to its receptor, programmed cell death protein 1 (PD-1), resulting in complex effects on the immune system (Chamoto et al, 2017; Wei et al, 2018). The putative mechanism put forward was that PD-1 blockage led to the recruitment of monocyte-derived macrophages to the brain, which cleared Aβ resulting in improved cognition. Following these interesting findings, several pharmaceutical companies that were developing PD-1 antibody blockers for other conditions pursued this approach with their own compounds and in different Aβ plaque mouse models. Several pharmaceutical companies that were developing PD-1 antibody blockers for other conditions pursued this approach with their own compounds and in different Aβ plaque mouse models In their hands, PD-1 immunotherapy stimulated systemic activation of the peripheral immune system as expected, but monocyte-derived macrophage infiltration
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