Microglia-mediated neuroinflammation is a common feature of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Microglia can be categorized into two opposite types: classical (M1) or alternative (M2), though there’s a continuum of different intermediate phenotypes between M1 and M2, and microglia can transit from one phenotype to another. M1 microglia release inflammatory mediators and induce inflammation and neurotoxicity, while M2 microglia release anti-inflammatory mediators and induce anti-inflammatory and neuroprotectivity. Microglia-mediated neuroinflammation is considered as a double-edged sword, performing both harmful and helpful effects in neurodegenerative diseases. Previous studies showed that balancing microglia M1/M2 polarization had a promising therapeutic prospect in neurodegenerative diseases. We suggest that shifting microglia from M1 to M2 may be significant and we focus on the modulation of microglia polarization from M1 to M2, especially by important signal pathways, in neurodegenerative diseases.

Nicotine plays a role in inhibiting the in ammatory factors, which contributes to improving cognitive impairment by activating α 4 β 2 nAChRs in ischemic rats, but the underling mechanism has not been fully elucidated. Janus tyrosine kinase 2-signal transducer and activator of transcription 3 (JAK2-STAT3) signaling pathway is involved in cognitive improvement, and there seems a relationship between nAChRs and JAK2-STAT3 as well. This study was designed to investigate the role of JAK2-STAT3 signaling pathway in nicotine-mediated anti-in ammation effect. Nicotine, DHβE (the most potent competitive antagonist of α 4 β 2 nAChRs) and AG490 (a speci c JAK2-STAT3 blocker) were adopted for intervention treatment in ischemic rats and HEK-293T-hα 4 β 2 cells. Morris Water Maze (MWM) test and 2-[18F]-A-85380 PET imaging were performed to detect the cognition and α 4 β 2 nAChRs in ischemic rats. The results demonstrated that nicotine intervention increased the density of α 4 β 2 nAChRs and improved cognitive impairment, but this effect would be blocked by AG490, while receptors were still upregulated.Essentially, when JAK2-STAT3 signaling pathway was blocked, nicotine could only upregulate the expression of α 4 β 2 nAChRs, but not improve the cognitive function. The results were further con rmed by PCR and Western blot analysis. The cell experiments also showed that nicotine could reduce in ammatory factors stimulated by LPS and upregulate the expression of pJAK2 and pSTAT3 in HEK-293T-hα 4 β 2 cells, while AG490 and DHβE reversed nicotine's effect. In summary, our work indicated that JAK2-STAT3 signaling pathway played an important role in nicotine-induced cognitive improvement by up-regulating α 4 β 2 nAChRs in ischemic rats.

Nicotine plays a role in inhibiting the inflammatory factors, which contributes to improving cognitive impairment by activating α4β2 nAChRs in ischemic rats, but the underling mechanism has not been fully elucidated. Janus tyrosine kinase 2-signal transducer and activator of transcription 3 (JAK2-STAT3) signaling pathway is involved in cognitive improvement, and there seems a relationship between nAChRs and JAK2-STAT3 as well. This study was designed to investigate the role of JAK2-STAT3 signaling pathway in nicotine-mediated anti-inflammation effect. Nicotine, DHβE (the most potent competitive antagonist of α4β2 nAChRs) and AG490 (a specific JAK2-STAT3 blocker) were adopted for intervention treatment in ischemic rats and HEK-293T-hα4β2 cells. Morris Water Maze (MWM) test and 2-[18F]-A-85380 PET imaging were performed to detect the cognition and α4β2 nAChRs in ischemic rats. The results demonstrated that nicotine intervention increased the density of α4β2 nAChRs and improved cognitive impairment, but this effect would be blocked by AG490, while receptors were still upregulated. Essentially, when JAK2-STAT3 signaling pathway was blocked, nicotine could only upregulate the expression of α4β2 nAChRs, but not improve the cognitive function. The results were further confirmed by PCR and Western blot analysis. The cell experiments also showed that nicotine could reduce inflammatory factors stimulated by LPS and upregulate the expression of pJAK2 and pSTAT3 in HEK-293T-hα4β2 cells, while AG490 and DHβE reversed nicotine’s effect. In summary, our work indicated that JAK2-STAT3 signaling pathway played an important role in nicotine-induced cognitive improvement by up-regulating α4β2 nAChRs in ischemic rats.