Journal Article

DZNE-2022-00156

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Microglial PD-1 stimulation by astrocytic PD-L1 suppresses neuroinflammation and Alzheimer's disease pathology.

Kummer, M. P.Extern* ; Ising, C.DZNE* ; Kummer, C. ; Sarlus, H.DZNE* ; Griep, A.DZNE* ; Vieira-Saecker, A.Extern* ; Schwartz, S.Extern* ; Halle, A.DZNE* ; Brückner, M.Extern* ; Händler, K.DZNE* ; Schultze, J. L.DZNE* ; Beyer, M.-D.DZNE* ; Latz, E.DZNE* ; Heneka, M. (Last author)DZNE*

2021
Wiley Hoboken, NJ [u.a.]

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Please use a persistent id in citations: doi:10.15252/embj.2021108662

Abstract: 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.

Keyword(s): Aged (MeSH) ; Aged, 80 and over (MeSH) ; Alzheimer Disease: genetics (MeSH) ; Alzheimer Disease: immunology (MeSH) ; Amyloid beta-Protein Precursor: genetics (MeSH) ; Amyloid beta-Protein Precursor: toxicity (MeSH) ; Animals (MeSH) ; Astrocytes: metabolism (MeSH) ; B7-H1 Antigen: metabolism (MeSH) ; CD36 Antigens: metabolism (MeSH) ; Case-Control Studies (MeSH) ; Disease Models, Animal (MeSH) ; Female (MeSH) ; Gene Deletion (MeSH) ; HEK293 Cells (MeSH) ; HeLa Cells (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Mice, Transgenic (MeSH) ; Microglia: metabolism (MeSH) ; Middle Aged (MeSH) ; Programmed Cell Death 1 Receptor: genetics (MeSH) ; Programmed Cell Death 1 Receptor: metabolism (MeSH) ; Up-Regulation (MeSH) ; 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

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Contributing Institute(s):

1. Interventional Trials and Biomarkers in Neurodegenerative Diseases (Biomarker)
2. Neuroinflammation, Biomarker (AG Heneka)
3. Microglia and Neuroinflammation (AG Halle)
4. Immunogenomics and Neurodegeneration (AG Beyer)
5. Innate Immunity in Neurodegeneration (AG Latz)
6. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
7. Platform for Single Cell Genomics and Epigenomics (PRECISE)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)
3. 351 - Brain Function (POF4-351) (POF4-351)
4. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2021

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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