@article{483351696d0e4189b9b94afe4aae32c9,
title = "ApoE attenuates unresolvable inflammation by complex formation with activated C1q",
abstract = "Apolipoprotein-E (ApoE) has been implicated in Alzheimer{\textquoteright}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 (K D~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.",
keywords = "A-BETA, ALZHEIMERS-DISEASE, APOLIPOPROTEIN-E, ATHEROSCLEROSIS, FACTOR-H BINDS, IMMUNE, LASER-CAPTURE MICRODISSECTION, MICE, NEURODEGENERATION, NEUROFIBRILLARY PATHOLOGY, Laser-capture microdissection, Apolipoprotein-e, Immune, A-beta, Neurodegeneration, Atherosclerosis, Neurofibrillary pathology, Mice, Alzheimers-disease, Factor-h binds",
author = "Changjun Yin and Susanne Ackermann and Zhe Ma and Mohanta, {Sarajo K.} and Chuankai Zhang and Yuanfang Li and Sandor Nietzsche and Martin Westermann and Li Peng and Desheng Hu and Bontha, {Sai Vineela} and Prasad Srikakulapu and Michael Beer and Megens, {Remco T. A.} and Sabine Steffens and Markus Hildner and Halder, {Luke D.} and Hans-Henning Eckstein and Jaroslav Pelisek and Jochen Herms and Sigrun Roeber and Thomas Arzberger and Anna Borodovsky and Livia Habenicht and Binder, {Christoph J.} and Christian Weber and Zipfel, {Peter F.} and Christine Skerka and Habenicht, {Andreas J. R.}",
note = "Funding Information: We thank W. Schneider, Medical University of Vienna, Austria, for advice; T. Hallstr{\"o}m, Y. Lin, and S. H{\"a}lbich, Leibniz Institute for Natural Product Research and Infection Biology, Jena, for performing complement assays; W. Wilfert, Institute of Laboratory Medicine, University of Munich for lipid analyses; S. Schmidt, Institute for Experimental Neurology, Jena, for advice; and N. Buresch, Center for Neuropathology and Prion Research, Munich, for technical assistance; M. Jucker, Hertie Institute for Clinical Brain Research, University of T{\"u}bingen, for experimental support. This work was funded by the Deutsche Forschungsgemeinschaft (DFG): YI 133/2-1 to C.Y.; HA 1083/15-4 to A.J.R.H.; MO 3054/1-1 to S.M.; The German Collaborative Research Center (CRC124/2-C4), SK46/2 to C.S.; CRC124/2-C6 and DFG TR 1992 to P.F.Z.; the German Centre for Cardiovascular Research (DZHK MHA VD1.2), DFG SFB 1123/A1 and Z3, the European Research Council (ERC AdG 692511) to C.W.; SFB1123/Z01, INST409/150-1 FUGG to R.T.A.M.; Chinese National Natural Science Foundation (31770983) to D.H.; S.A. and L.D.H. are doctoral researchers at the International Leibniz Research School (ILRS) in Jena. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = mar,
day = "1",
doi = "10.1038/s41591-018-0336-8",
language = "English",
volume = "25",
pages = "496--506",
journal = "Nature Medicine",
issn = "1078-8956",
publisher = "Nature Research",
number = "3",
}