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

doi:10.1038/s41591-018-0336-8

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 HermsSigrun Roeber, Thomas Arzberger, Anna Borodovsky, Livia Habenicht, Christoph J. Binder, Christian Weber, Peter F. Zipfel, Christine Skerka^*, Andreas J. R. Habenicht

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

130 Citations (Web of Science)

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.

Original language	English
Pages (from-to)	496-506
Number of pages	23
Journal	Nature Medicine
Volume	25
Issue number	3
DOIs	https://doi.org/10.1038/s41591-018-0336-8
Publication status	Published - Mar 2019

Keywords

LASER-CAPTURE MICRODISSECTION
FACTOR-H BINDS
APOLIPOPROTEIN-E
ALZHEIMERS-DISEASE
A-BETA
NEUROFIBRILLARY PATHOLOGY
ATHEROSCLEROSIS
IMMUNE
MICE
NEURODEGENERATION

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10.1038/s41591-018-0336-8

130 Citations
1 Erratum / corrigendum / retractions

Publisher Correction: ApoE attenuates unresolvable inflammation by complex formation with activated C1q
Yin, C., Ackermann, S., Ma, Z., Mohanta, S. K., Zhang, C., Li, Y., Nietzsche, S., Westermann, M., Peng, L., Hu, D., Bontha, S. V., Srikakulapu, P., Beer, M., Megens, R. T. A., Steffens, S., Hildner, M., Halder, L. D., Eckstein, H-H., Pelisek, J., Herms, J., & 9 othersRoeber, S., Arzberger, T., Borodovsky, A., Habenicht, L., Binder, C. J., Weber, C., Zipfel, P. F., Skerka, C. & Habenicht, A. J. R., Mar 2019, In: Nature Medicine. 25, 3, p. 529-529 1 p.
Research output: Contribution to journal › Erratum / corrigendum / retractions › Academic

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4 Citations (Web of Science)

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Yin, C., Ackermann, S., Ma, Z., Mohanta, S. K., Zhang, C., Li, Y., Nietzsche, S., Westermann, M., Peng, L., Hu, D., Bontha, S. V., Srikakulapu, P., Beer, M., Megens, R. T. A., Steffens, S., Hildner, M., Halder, L. D., Eckstein, H-H., Pelisek, J., ... 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

@article{483351696d0e4189b9b94afe4aae32c9,

title = "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 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.",

keywords = "LASER-CAPTURE MICRODISSECTION, FACTOR-H BINDS, APOLIPOPROTEIN-E, ALZHEIMERS-DISEASE, A-BETA, NEUROFIBRILLARY PATHOLOGY, ATHEROSCLEROSIS, IMMUNE, MICE, NEURODEGENERATION",

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.}",

year = "2019",

month = mar,

doi = "10.1038/s41591-018-0336-8",

language = "English",

volume = "25",

pages = "496--506",

journal = "Nature Medicine",

issn = "1078-8956",

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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, H-H, 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

TY - JOUR

T1 - ApoE attenuates unresolvable inflammation by complex formation with activated C1q

AU - Yin, Changjun

AU - Ackermann, Susanne

AU - Ma, Zhe

AU - Mohanta, Sarajo K.

AU - Zhang, Chuankai

AU - Li, Yuanfang

AU - Nietzsche, Sandor

AU - Westermann, Martin

AU - Peng, Li

AU - Hu, Desheng

AU - Bontha, Sai Vineela

AU - Srikakulapu, Prasad

AU - Beer, Michael

AU - Megens, Remco T. A.

AU - Steffens, Sabine

AU - Hildner, Markus

AU - Halder, Luke D.

AU - Eckstein, Hans-Henning

AU - Pelisek, Jaroslav

AU - Herms, Jochen

AU - Roeber, Sigrun

AU - Arzberger, Thomas

AU - Borodovsky, Anna

AU - Habenicht, Livia

AU - Binder, Christoph J.

AU - Weber, Christian

AU - Zipfel, Peter F.

AU - Skerka, Christine

AU - Habenicht, Andreas J. R.

PY - 2019/3

Y1 - 2019/3

N2 - 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.

AB - 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.

KW - LASER-CAPTURE MICRODISSECTION

KW - FACTOR-H BINDS

KW - APOLIPOPROTEIN-E

KW - ALZHEIMERS-DISEASE

KW - A-BETA

KW - NEUROFIBRILLARY PATHOLOGY

KW - ATHEROSCLEROSIS

KW - IMMUNE

KW - MICE

KW - NEURODEGENERATION

U2 - 10.1038/s41591-018-0336-8

DO - 10.1038/s41591-018-0336-8

M3 - Article

C2 - 30692699

SN - 1078-8956

VL - 25

SP - 496

EP - 506

JO - Nature Medicine

JF - Nature Medicine

IS - 3

ER -

ApoE attenuates unresolvable inflammation by complex formation with activated C1q

Abstract

Keywords

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Research output

Publisher Correction: ApoE attenuates unresolvable inflammation by complex formation with activated C1q

Cite this