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 Ca2+ 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 Ca2+ 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.
Highlights
Neuro-inflammation accompanies and often precedes the development of neurodegenerative pathologies such as Parkinson’s and Alzheimer’s diseases (AD; Wee Yong, 2010) and might be one of the pathogenic factors for neurodegeneration (Chung et al, 2010; Heppner et al, 2015)
Our findings indicate that LPS down-regulates α7 nAChR and AChE in the brain; exacerbates the mitochondrial pathway of apoptosis and changes brain miRNAs in favor of pro-apoptotic and anti-inflammatory ones
Sandwich ELISA performed with whole brain preparations demonstrated that LPS treatment decreased the level of α7 nAChR subunits while increasing the α3 and β4 subunits
Summary
Neuro-inflammation accompanies and often precedes the development of neurodegenerative pathologies such as Parkinson’s and Alzheimer’s diseases (AD; Wee Yong, 2010) and might be one of the pathogenic factors for neurodegeneration (Chung et al, 2010; Heppner et al, 2015). A number of studies point out the involvement of α7 nAChRs in pro-survival cell signaling, engaging the PI3K/Akt signaling pathway (Parada et al, 2010; Yu et al, 2011; Cucina et al, 2012; Huang et al, 2012; Cui et al, 2013). Such signaling was shown to protect cultured brain cells from apoptosis induced by various apoptogenic agents (Parada et al, 2010). Α7 nAChRs were found to regulate mitochondrial permeability transition pore formation and release of apoptogenic factors like cytochrome (cyt c) and to control the mitochondrialmediated pathway of apoptosis (Gergalova et al, 2012, 2014)
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