APP; PD-1 knockout mice; PS1 mice; innate immune system; microglia; APP protein, human; Amyloid beta-Protein Precursor; B7-H1 Antigen; CD274 protein, human; CD36 Antigens; CD36 protein, human; PDCD1 protein, human; Programmed Cell Death 1 Receptor; Aged; Aged, 80 and over; Alzheimer Disease/genetics; Alzheimer Disease/immunology; Amyloid beta-Protein Precursor/genetics; Amyloid beta-Protein Precursor/toxicity; Animals; Astrocytes/metabolism; B7-H1 Antigen/metabolism; CD36 Antigens/metabolism; Case-Control Studies; Disease Models, Animal; Female; Gene Deletion; HEK293 Cells; HeLa Cells; Humans; Male; Mice; Mice, Transgenic; Microglia/metabolism; Middle Aged; Programmed Cell Death 1 Receptor/genetics; Programmed Cell Death 1 Receptor/metabolism; Up-Regulation; Alzheimer Disease; Astrocytes; Neuroscience (all); Molecular Biology; Biochemistry, Genetics and Molecular Biology (all); Immunology and Microbiology (all); General Immunology and Microbiology; General Biochemistry, Genetics and Molecular Biology; General Neuroscience
Abstract :
[en] Chronic neuroinflammation is a pathogenic component of Alzheimer's disease (AD) that may limit the ability of the brain to clear amyloid deposits and cellular debris. Tight control of the immune system is therefore key to sustain the ability of the brain to repair itself during homeostasis and disease. The immune-cell checkpoint receptor/ligand pair PD-1/PD-L1, known for their inhibitory immune function, is expressed also in the brain. Here, we report upregulated expression of PD-L1 and PD-1 in astrocytes and microglia, respectively, surrounding amyloid plaques in AD patients and in the APP/PS1 AD mouse model. We observed juxtamembrane shedding of PD-L1 from astrocytes, which may mediate ectodomain signaling to PD-1-expressing microglia. Deletion of microglial PD-1 evoked an inflammatory response and compromised amyloid-β peptide (Aβ) uptake. APP/PS1 mice deficient for PD-1 exhibited increased deposition of Aβ, reduced microglial Aβ uptake, and decreased expression of the Aβ receptor CD36 on microglia. Therefore, ineffective immune regulation by the PD-1/PD-L1 axis contributes to Aβ plaque deposition during chronic neuroinflammation in AD.
Disciplines :
Neurology
Author, co-author :
Kummer, Markus P ; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn Medical Faculty, Bonn, Germany
Ising, Christina ; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn Medical Faculty, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Kummer, Christiane; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn Medical Faculty, Bonn, Germany
Sarlus, Heela ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Griep, Angelika; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Vieira-Saecker, Ana; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn Medical Faculty, Bonn, Germany
Schwartz, Stephanie; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn Medical Faculty, Bonn, Germany
Halle, Annett; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Brückner, Matthias; Caesar Research Center, Bonn, Germany
Händler, Kristian; Systems Medicine, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; PRECISE Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases (DZNE) and University of Bonn, Bonn, Germany
Schultze, Joachim L; Systems Medicine, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; PRECISE Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases (DZNE) and University of Bonn, Bonn, Germany ; Genomics and Immunoregulation, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
Beyer, Marc ; PRECISE Platform for Single Cell Genomics and Epigenomics, German Center for Neurodegenerative Diseases (DZNE) and University of Bonn, Bonn, Germany ; Molecular Immunology in Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Latz, Eicke; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Institute of Innate Immunity, University of Bonn, Bonn, Germany ; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA
HENEKA, Michael ; Department of Neurodegenerative Diseases and Geriatric Psychiatry, University of Bonn Medical Faculty, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA
We are grateful to Dr. Jochen Walter (University of Bonn) for providing the presenilin‐overexpressing HEK293. The synopsis image was created with BioRender.com. This study was supported by the Deutsche Forschungsgemeinschaft (KFO177, TP4) to MTH and by grants of the INMiND project of the Seventh Framework of the European Union. CI received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, IS 299/3‐1). MTH and CI are members of the Cluster of Excellence ImmunoSensation, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—EXC2151‐390873048. 2We are grateful to Dr. Jochen Walter (University of Bonn) for providing the presenilin-overexpressing HEK293. The synopsis image was created with BioRender.com. This study was supported by the Deutsche Forschungsgemeinschaft (KFO177, TP4) to MTH and by grants of the INMiND project of the Seventh Framework of the European Union. CI received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, IS 299/3-1). MTH and CI are members of the Cluster of Excellence ImmunoSensation2, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany?s Excellence Strategy?EXC2151-390873048.
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