ABSTRACT: A novel polysaccharide PSP2-1 was isolated and purified from Pleurotus sajor-caju. The structural characterization data displayed that the molecular weight of PSP2-1 was 44.9 kDa, and PSP2-1 consisted of fucose, galactose, glucose, and mannose. The methylation results showed that the glycosidic bonds of PSP2-1 included T-Fuc, 1,6-Gal, T-Glc, 1,6-Glc, 1,3,6-Glc, 1,3-Man, 1,2,6-Man, and T-Man. Neuroprotective studies indicated that PSP2-1 significantly improved the cell viability of the H2O2-induced oxidatively damaged neuronal cell HT22, reduced the release of LDH, inhibited apoptosis and release of cytochrome c, and alleviated the decline of mitochondrial membrane potential and ROS accumulation. Furthermore, PSP2-1 decreased the phosphorylation levels of cleave