ApoE attenuates unresolvable inflammation by complex formation with activated C1q.

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.

• Authors: Changjun Yin, Susanne Ackermann, Zhe Ma, Sarajo K Mohanta, Chuankai Zhang, Yuanfang Li, Sandor Nietzsche, Martin Westermann, Li Peng, Desheng Hu, Sai Vineela Bontha, Prasad Srikakulapu, Michael Beer, Remco T A Megens, Sabine Steffens, Markus Hildner, Luke D Halder, Hans-Henning Eckstein, Jaroslav Pelisek, Jochen Herms, Sigrun Roeber, Thomas Arzberger, Anna Borodovsky, Livia Habenicht, Christoph J Binder, Christian Weber, Peter F Zipfel, Christine Skerka, Andreas J R Habenicht
• Journal: Nature medicine (Nat Med) Vol. 25 Issue 3 Pg. 496-506 (03 2019) ISSN: 1546-170X [Electronic] United States
• PMID: 30692699 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Video-Audio Media)

Chemical References

• Amyloid beta-Peptides
• Antigen-Antibody Complex
• ApoE protein, human
• Apolipoproteins E
• Complement C5
• Protein Isoforms
• RNA, Small Interfering
• Complement C1q

Topics

• Aged
• Aged, 80 and over
• Amyloid beta-Peptides (immunology)
• Animals
• Antigen-Antibody Complex (immunology)
• Aorta (immunology, pathology)
• Apolipoproteins E (immunology)
• Atherosclerosis (immunology, pathology)
• Brain (immunology, pathology)
• Carotid Arteries (immunology, pathology)
• Carotid Artery Diseases (immunology, pathology)
• Choroid Plexus (immunology, pathology)
• Cognitive Dysfunction (immunology, pathology)
• Complement C1q (immunology)
• Complement C5
• Complement Pathway, Classical (immunology)
• Female
• Humans
• Leukocytes
• Male
• Mice, Knockout, ApoE
• Microscopy, Fluorescence
• Middle Aged
• Plaque, Amyloid (immunology, pathology)
• Protein Isoforms (immunology)
• RNA, Small Interfering