Introduction: Oligodendrocyte precursor cells (OPCs) differentiation dysfunction is closely related to demyelinating diseases and cognitive dysfunction. P75 neurotrophin receptor (P75NTR) is a prototypical co-receptor that induces Schwann cell death via γ-secretase-dependent regulated intramembrane proteolysis. This study hypothesizes that P75NTR may also assists in inhibiting OPCs differentiation.Methods Male C57BL/6 mice were fed 0.2% cuprizone (CPZ) continuously for 6 weeks to establish the acute demyelinating model (CPZ mice). Morris Water Maze and Elevated Plus Maze tests were used to assess the behavioral changes of these mice. Immunohistochemistry and Western blot were used to detect the OPCs and oligodendrocytes (OLs) protein markers. Furthermore, γ-secretase inhibitor DAPT (GSI-IX) was injected into the hippocampus at the fifth week of establishing the demyelinating model to investigate the effects of DAPT on OPCs differentiation and the mice’s behavioral changes.Results CPZ mice performed abnormal behavioral changes, and the protein expression of the OLs marker 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase) decreased. However, the OPCs marker neural/glial antigen 2 (NG2) protein expression increased. After DAPT treatment, the abnormal behavior improved, CNPase increased, and NG2 decreased.Conclusions P75 cleavage plays an inhibitory role during the OPCs differentiation resulting in inefficient OPCs differentiation and recurrent demyelinating diseases.

Background Alcohol can cause neuroinflammation, leading to neuron damage and further memory and cognitive impairment. Recent animal studies have shown that the exposure to chronic alcohol consumption induces robust inflammatory microglial activation in the brain. However, as a novel anti-inflammation approach, the impact of sodium butyrate on chronic alcohol-induced neuroinflammation still remains unclear. Methods Sixty female C57BL/6J mice were randomly divided into 4 groups: pair-fed (PF) group (PF/CON), alcohol-fed (AF) group (AF/CON), PF with sodium butyrate (NaB) group (PF/NaB) and AF with NaB group (AF/NaB). Each group was fed a modified Lieber-DeCarli liquid diet with or without alcohol. Mice were subjected to different behavioral tests to assess aberrant behaviours (deficits in cognitive functions, depression and anxiety). Pathological changes were further investigated by Hematoxylin and eosin staining (HE) and Nissl staining. The microglial activation and microglial polarization were observed by immunohistochemistry (IHC), immunofluorescence (IF) and flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of inflammatory factors. G-protein coupled receptor 109A (GPR109A), peroxisome proliferator-activated receptor γ (PPAR-γ) and nuclear factor-κB (NF-κB) mRNA and protein levels were evaluated by reverse transcription‑quantitative (RT‑q) PCR and western blot (WB). Results As indicated by the behavioural tests, inflammatory indicators, microglial activation (M1/M2 microglia polarization) and brain morphology, sodium butyrate administration ameliorated aberrant behaviours (locomotor hypoactivity, anxiety disorders and depressive behaviours, impaired learning and spatial recognition memory), effectively reduced neuroinflammation and neuronal damage. The effectiveness of sodium butyrate may attribute to the GPR109A receptor in microglia by up-regulating the expression of PPAR-γ and inhibiting the activation of NF-κB. Conclusion Sodium butyrate ameliorates neuroinflammation induced by chronic alcohol exposure and improves memory and cognitive functions in mice via modulating microglia-mediated GPR109A / PPAR-γ / NF-κB signaling pathway.