ApoE attenuates unresolvable inflammation by complex formation with activated C1q.
Nat Med
; 25(3): 496-506, 2019 03.
Article
de En
| MEDLINE
| ID: mdl-30692699
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, Aß plaques, and atherosclerosis in vivo. C1q-ApoE complexes in human ChPs, Aß 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, Aß-associated microglia accumulation, and atherosclerosis. Thus, ApoE is a direct checkpoint inhibitor of unresolvable inflammation, and reducing C5 attenuates disease burden.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Apolipoprotéines E
/
Artériopathies carotidiennes
/
Complément C1q
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Plexus choroïde
/
Voie classique d'activation du complément
/
Dysfonctionnement cognitif
/
Complexe antigène-anticorps
Limites:
Aged
/
Aged80
/
Animals
/
Female
/
Humans
/
Male
/
Middle aged
Langue:
En
Journal:
Nat Med
Sujet du journal:
BIOLOGIA MOLECULAR
/
MEDICINA
Année:
2019
Type de document:
Article
Pays d'affiliation:
Allemagne