Journal
NATURE MEDICINE
Volume 25, Issue 3, Pages 496-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-018-0336-8
Keywords
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [YI 133/2-1, HA 1083/15-4, MO 3054/1-1]
- German Collaborative Research Center [CRC124/2-C4, SK46/2, CRC124/2-C6]
- DFG [TR 1992, SFB 1123/A1, SFB 1123/Z3]
- German Centre for Cardiovascular Research [DZHK MHA VD1.2]
- European Research Council (ERC) [AdG 692511, SFB1123/Z01, INST409/150-1 FUGG]
- Chinese National Natural Science Foundation [31770983]
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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.
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