PANoptosis inhibition by Morchella sextelata polysaccharide mediates neuroprotection in Alzheimer's disease models.

PANoptosis has been hypothesized to play a role in the pathogenesis of Alzheimer's disease (AD), with potential contributions to neuronal dysfunction and loss. This study aims to analyze the structural characteristics of Morchella sextelata polysaccharide (MSP) and to investigate its neuroprotective properties and the pathways implicated in AD pathology. The main chain of the MSP polysaccharide, with a molecular weight of 2283.3 kDa, consists of →4)-α-D-Glcp-(1 → and →4,6)-β-D-Glcp-(1 → linkages, and α-D-Glcp-(1 → connected as a branched chain to the O-4 position of →4,6)-β-D-Glcp-(1→. In behavioral tests, MSP enhances memory and cognitive function in mice, and it inhibits the production of Aβ in the mouse brain. Furthermore, proteomic and metabolomic analyses indicate that MSP may exert inhibitory effects on PANoptosis. Evidence shows that MSP suppresses pyroptosis induced by the NLRP3 inflammasome, apoptosis mediated by the caspase protein family, and necroptosis dependent on RIPK1. Overall, administration of MSP leads to significant improvements in memory and attenuation of brain pathology in APP/PS1 mice, effects that are attributed to its inhibition of PANoptosis.