ApoE attenuates unresolvable inflammation by complex formation with activated C1q

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 & 9 others Sigrun Roeber, Thomas Arzberger, Anna Borodovsky, Livia Habenicht, Christoph J. Binder, Christian Weber, Peter F. Zipfel, Christine Skerka, Andreas J.R. Habenicht

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)496-506
Number of pages11
JournalNature Medicine
Volume25
Issue number3
DOIs
StatePublished - Mar 1 2019

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Apolipoproteins E
Atherosclerosis
Inflammation
Choroid Plexus
Microglia
Infiltration
Small Interfering RNA
Alzheimer Disease
Protein Isoforms
Leukocytes
Arteries
Lipids
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Yin, C., Ackermann, S., Ma, Z., Mohanta, S. K., Zhang, C., Li, Y., ... Habenicht, A. J. R. (2019). ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nature Medicine, 25(3), 496-506. https://doi.org/10.1038/s41591-018-0336-8

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; Habenicht, Andreas J.R.

In: Nature Medicine, Vol. 25, No. 3, 01.03.2019, p. 496-506.

Research output: Contribution to journalArticle

Yin, C, Ackermann, S, Ma, Z, Mohanta, SK, Zhang, C, Li, Y, Nietzsche, S, Westermann, M, Peng, L, Hu, D, Bontha, SV, Srikakulapu, P, Beer, M, Megens, RTA, Steffens, S, Hildner, M, Halder, LD, Eckstein, HH, Pelisek, J, Herms, J, Roeber, S, Arzberger, T, Borodovsky, A, Habenicht, L, Binder, CJ, Weber, C, Zipfel, PF, Skerka, C & Habenicht, AJR 2019, 'ApoE attenuates unresolvable inflammation by complex formation with activated C1q', Nature Medicine, vol. 25, no. 3, pp. 496-506. https://doi.org/10.1038/s41591-018-0336-8
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 ; Habenicht, Andreas J.R. / ApoE attenuates unresolvable inflammation by complex formation with activated C1q. In: Nature Medicine. 2019 ; Vol. 25, No. 3. pp. 496-506.
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AU - Borodovsky, Anna

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AU - Binder, Christoph J.

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