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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.

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