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Nat Med. 2019 Jan 28. doi: 10.1038/s41591-018-0336-8. [Epub ahead of print]

ApoE attenuates unresolvable inflammation by complex formation with activated C1q.

Author information

1
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany. changjun.yin@med.uni-muenchen.de.
2
German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany. changjun.yin@med.uni-muenchen.de.
3
Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany.
4
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich, Germany.
5
Centre for Electron Microscopy, Jena University Hospital, Friedrich-Schiller-University of Jena, Jena, Germany.
6
Department of Cardiovascular Medicine of Second Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, China.
7
Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
8
Department of Surgery, University of Tennessee, Memphis, TN, USA.
9
Cardiovascular Research Center (CVRC), University of Virginia, Charlottesville, VA, USA.
10
Department of Information Technology, University Clinic Jena, Jena, Germany.
11
Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands.
12
German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.
13
Institute for Anatomy II, University Clinic Jena, Jena, Germany.
14
Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
15
Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany.
16
Munich Cluster of Systems Neurology (SyNergy), Ludwig-Maximilians-University, Munich, Germany.
17
Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich, Germany.
18
Alnylam Pharmaceuticals Cambridge, Cambridge, MA, USA.
19
II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
20
Department of Laboratory Medicine, Medical University of Vienna and Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria.
21
Friedrich-Schiller-University, Faculty of Biological Sciences, Jena, Germany.
22
Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany. christine.skerka@hki-jena.de.

Abstract

Apolipoprotein-E (ApoE) has been implicated in Alzheimer's disease, atherosclerosis, and other unresolvable inflammatory conditions but a common mechanism of action remains elusive. We found in ApoE-deficient mice that oxidized lipids activated the classical complement cascade (CCC), resulting in leukocyte infiltration of the choroid plexus (ChP). All human ApoE isoforms attenuated CCC activity via high-affinity binding to the activated CCC-initiating C1q protein (KD~140-580 pM) in vitro, and C1q-ApoE complexes emerged as markers for ongoing complement activity of diseased ChPs, Aβ plaques, and atherosclerosis in vivo. C1q-ApoE complexes in human ChPs, Aβ plaques, and arteries correlated with cognitive decline and atherosclerosis, respectively. Treatment with small interfering RNA (siRNA) against C5, which is formed by all complement pathways, attenuated murine ChP inflammation, Aβ-associated microglia accumulation, and atherosclerosis. Thus, ApoE is a direct checkpoint inhibitor of unresolvable inflammation, and reducing C5 attenuates disease burden.

PMID:
30692699
DOI:
10.1038/s41591-018-0336-8

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