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Chronic PD-1 Checkpoint Blockade Does Not Affect Cognition or Promote Tau Clearance in a Tauopathy Mouse Model
Yan Lin1, Hameetha B Rajamohamedsait1, Leslie A Sandusky-Beltran1
1Department of Neuroscience and Physiology, Neuroscience Institute, New York University School of Medicine, New York, NY, United States.
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.
Insights
Programmed cell death protein 1 (PD-1) checkpoint blockade showed promise in some mouse models. However, this study found no cognitive or tau pathology benefits in a common tauopathy model, suggesting more research is needed.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Programmed cell death protein 1 (PD-1) checkpoint blockade has shown potential in reducing amyloid-β plaques and improving cognition in certain mouse models.
- Previous studies reported benefits in tauopathy models, but subsequent research yielded conflicting results in amyloid-β models.
Purpose of the Study:
- To investigate the efficacy of PD-1 checkpoint blockade in a commonly used tauopathy mouse model.
- To assess the effects of PD-1 antibody treatment on cognition, tau pathology, and locomotor activity.
Main Methods:
- Mice with tauopathy were treated weekly for 12 weeks with a PD-1 antibody or an isotype control.
- Cognitive function, tau pathology, and locomotor activity were evaluated post-treatment.
Main Results:
- A modest increase in locomotor activity was observed.
- No significant improvements in cognition or reduction in tau pathology were detected.
- The results differed from previous positive findings in other tauopathy models.
Conclusions:
- PD-1 checkpoint immune blockade may not be universally effective for all tauopathy models.
- Further research is required to understand the mechanisms and identify patient populations that may benefit from this immunotherapy.
- Clinical trials for tauopathies based on PD-1 blockade should be approached with caution pending further investigation.
