%0 Journal Article
%A Kummer, Markus P.
%A Ising, Christina
%A Kummer, Christiane
%A Sarlus, Heela
%A Griep, Angelika
%A Vieira-Saecker, Ana
%A Schwartz, Stephanie
%A Halle, Annett
%A Brückner, Matthias
%A Händler, Kristian
%A Schultze, Joachim L
%A Beyer, Marc-Daniel
%A Latz, Eicke
%A Heneka, Michael
%T Microglial PD-1 stimulation by astrocytic PD-L1 suppresses neuroinflammation and Alzheimer's disease pathology.
%J The EMBO journal
%V 40
%N 24
%@ 1460-2075
%C Hoboken, NJ [u.a.]
%I Wiley
%M DZNE-2022-00156
%P e108662
%D 2021
%X 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.
%K Aged
%K Aged, 80 and over
%K Alzheimer Disease: genetics
%K Alzheimer Disease: immunology
%K Amyloid beta-Protein Precursor: genetics
%K Amyloid beta-Protein Precursor: toxicity
%K Animals
%K Astrocytes: metabolism
%K B7-H1 Antigen: metabolism
%K CD36 Antigens: metabolism
%K Case-Control Studies
%K Disease Models, Animal
%K Female
%K Gene Deletion
%K HEK293 Cells
%K HeLa Cells
%K Humans
%K Male
%K Mice
%K Mice, Transgenic
%K Microglia: metabolism
%K Middle Aged
%K Programmed Cell Death 1 Receptor: genetics
%K Programmed Cell Death 1 Receptor: metabolism
%K Up-Regulation
%K APP (Other)
%K PD-1 knockout mice (Other)
%K PS1 mice (Other)
%K innate immune system (Other)
%K microglia (Other)
%K APP protein, human (NLM Chemicals)
%K Amyloid beta-Protein Precursor (NLM Chemicals)
%K B7-H1 Antigen (NLM Chemicals)
%K CD274 protein, human (NLM Chemicals)
%K CD36 Antigens (NLM Chemicals)
%K CD36 protein, human (NLM Chemicals)
%K PDCD1 protein, human (NLM Chemicals)
%K Programmed Cell Death 1 Receptor (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:34825707
%2 pmc:PMC8672180
%R 10.15252/embj.2021108662
%U https://pub.dzne.de/record/163394