ApoE attenuates unresolvable inflammation by complex formation with activated C1q

Yin, Changjun; Ackermann, Susanne; Ma, Zhe; Mohanta, Sarajo K.; Zhang, Chuankai; Li, Yuanfang; Nietzsche, Sandor; Westermann, Martin; Peng, Li; Hu, Desheng; Bontha, Sai Vineela; Srikakulapu, Prasad; Beer, Michael; Megens, Remco T. A.; Steffens, Sabine; Hildner, Markus; Halder, Luke D.; Eckstein, Hans-Henning; Pelisek, Jaroslav; Herms, Jochen; Roeber, Sigrun; Arzberger, Thomas; Borodovsky, Anna; Habenicht, Livia; Binder, Christoph J.; Weber, Christian; Zipfel, Peter F.; Skerka, Christine und Habenicht, Andreas J. R. (2019): ApoE attenuates unresolvable inflammation by complex formation with activated C1q. In: Nature Medicine, Bd. 25, Nr. 3

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 iso-forms attenuated CCC activity via high-affinity binding to the activated CCC-initiating C1q protein (K-D similar to 140-580 pM) in vitro, and C1q-ApoE complexes emerged as markers for ongoing complement activity of diseased ChPs, A beta plaques, and atherosclerosis in vivo. C1q-ApoE complexes in human ChPs, A beta 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, A beta-associated microglia accumulation, and atherosclerosis. Thus, ApoE is a direct checkpoint inhibitor of unresolvable inflammation, and reducing C5 attenuates disease burden.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1078-8956
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198