title: Molecular Mechanisms Regulating LPS-Induced Inflammation in the Brain.
abstract: Neuro-inflammation, one of the pathogenic causes of neurodegenerative diseases, is regulated through the cholinergic anti-inflammatory pathway via the α7 nicotinic acetylcholine receptor (α7 nAChR). We previously showed that either bacterial lipopolysaccharide (LPS) or immunization with the α7(1-208) nAChR fragment decrease α7 nAChRs density in the mouse brain, exacerbating chronic inflammation, beta-amyloid accumulation and episodic memory decline, which mimic the early stages of Alzheimer's disease (AD). To study the molecular mechanisms underlying the LPS and antibody effects in the brain, we employed an in vivo model of acute LPS-induced inflammation and an in vitro model of cultured glioblastoma U373 cells. Here, we report that LPS challenge decreased the levels of α7 nAChR RNA and protein and of acetylcholinesterase (AChE) RNA and activity in distinct mouse brain regions, sensitized brain mitochondria to the apoptogenic effect of Ca(2+) and modified brain microRNA profiles, including the cholinergic-regulatory CholinomiRs-132/212, in favor of anti-inflammatory and pro-apoptotic ones. Adding α7(1-208)-specific antibodies to the LPS challenge prevented elevation of both the anti-inflammatory and pro-apoptotic miRNAs while supporting the resistance of brain mitochondria to Ca(2+) and maintaining α7 nAChR/AChE decreases. In U373 cells, α7-specific antibodies and LPS both stimulated interleukin-6 production through the p38/Src-dependent pathway. Our findings demonstrate that acute LPS-induced inflammation induces the cholinergic anti-inflammatory pathway in the brain, that α7 nAChR down-regulation limits this pathway, and that α7-specific antibodies aggravate neuroinflammation by inducing the pro-inflammatory interleukin-6 and dampening anti-inflammatory miRNAs; however, these antibodies may protect brain mitochondria and decrease the levels of pro-apoptotic miRNAs, preventing LPS-induced neurodegeneration.
authors.affiliation: Laboratory of Cell Receptors Immunology, O. V. Palladin Institute of Biochemistry Kyiv, Ukraine.
authors.forename: Olena
authors.initials: O
authors.lastname: Lykhmus
authors.affiliation: The Edmond and Lily Safra Center of Brain Science and The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem Jerusalem, Israel.
authors.forename: Nibha
authors.initials: N
authors.lastname: Mishra
authors.affiliation: Laboratory of Cell Receptors Immunology, O. V. Palladin Institute of Biochemistry Kyiv, Ukraine.
authors.forename: Lyudmyla
authors.initials: L
authors.lastname: Koval
authors.affiliation: Laboratory of Cell Receptors Immunology, O. V. Palladin Institute of Biochemistry Kyiv, Ukraine.
authors.forename: Olena
authors.initials: O
authors.lastname: Kalashnyk
authors.affiliation: Laboratory of Cell Receptors Immunology, O. V. Palladin Institute of Biochemistry Kyiv, Ukraine.
authors.forename: Galyna
authors.initials: G
authors.lastname: Gergalova
authors.affiliation: Laboratory of Cell Receptors Immunology, O. V. Palladin Institute of Biochemistry Kyiv, Ukraine.
authors.forename: Kateryna
authors.initials: K
authors.lastname: Uspenska
authors.affiliation: Laboratory of Cell Receptors Immunology, O. V. Palladin Institute of Biochemistry Kyiv, Ukraine.
authors.forename: Serghiy
authors.initials: S
authors.lastname: Komisarenko
authors.affiliation: The Edmond and Lily Safra Center of Brain Science and The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem Jerusalem, Israel.
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
authors.affiliation: Laboratory of Cell Receptors Immunology, O. V. Palladin Institute of Biochemistry Kyiv, Ukraine.
authors.forename: Maryna
authors.initials: M
authors.lastname: Skok
keywords: acetylcholine esterase; antibody; brain; inflammation; microRNA; α7 nicotinic acetylcholine receptor