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Updated: Oct 8, 2025
Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
Published on: November 9, 2018
Programmed Cell Death Protein 1 Blockade Reduces Glycogen Synthase Kinase 3β Activity and Tau Hyperphosphorylation in
Yulian Zou1, Chen-Ling Gan2,3, Zhiming Xin4
1Institute of Immunotherapy, Fujian Medical University, Fuzhou, China.
Abstract:
Alzheimer's disease (AD) is a central nervous system degenerative disease, with no effective treatment to date. Administration of immune checkpoint inhibitors significantly reduces neuronal damage and tau hyperphosphorylation in AD, but the specific mechanism is unclear. Here, we found that programmed cell death-receptor 1 (PD1) and its ligand PDL1 were induced by an intracerebroventricular injection of amyloid-β; they were significantly upregulated in the brains of APP/PS1, 5×FAD mice and in SH-SY5Y-APP cell line compared with control. The PD1 and PDL1 levels positively correlated with the glycogen synthase kinase 3 beta (GSK3β) activity in various AD mouse models, and the PDL1-GSK3β immune complex was found in the brain. The application of PD1-blocking antibody reduced tau hyperphosphorylation and GSK3β activity and prevented memory impairments. Mechanistically, we identified PD1 as a critical regulator of GSK3β activity. These results suggest that the immune regulation of the PD1/PDL1 axis is closely involved in AD.
Insights
The programmed cell death-receptor 1 (PD1)/PDL1 immune axis is implicated in Alzheimer's disease (AD). Targeting this axis reduced tau pathology and improved memory in AD models, suggesting a novel therapeutic avenue.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder with no effective treatments.
- Immune checkpoint inhibitors show promise in reducing AD-related neuronal damage and tau hyperphosphorylation, but mechanisms remain elusive.
Purpose of the Study:
- To investigate the role of the programmed cell death-receptor 1 (PD1) and its ligand PDL1 axis in Alzheimer's disease pathogenesis.
- To elucidate the mechanism by which PD1/PDL1 signaling influences neuroinflammation and tau pathology in AD.
Main Methods:
- Induction of amyloid-beta in mouse models and cell lines to study PD1 and PDL1 expression.
- Correlation analysis between PD1/PDL1 levels and glycogen synthase kinase 3 beta (GSK3β) activity.
- Administration of PD1-blocking antibodies in AD mouse models.
Main Results:
- PD1 and PDL1 were upregulated in AD mouse models and cell lines, correlating positively with GSK3β activity.
- A PDL1-GSK3β immune complex was detected in the brain.
- PD1 blockade reduced tau hyperphosphorylation, decreased GSK3β activity, and ameliorated memory deficits.
Conclusions:
- The PD1/PDL1 immune axis is a critical regulator of GSK3β activity in Alzheimer's disease.
- Targeting the PD1/PDL1 pathway represents a potential therapeutic strategy for AD by modulating tau pathology and cognitive decline.
