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Age-related macular degeneration (AMD) is a sight-threatening disease with limited treatment options. We investigated whether amyloid β_1-40 (Aβ_1-40) could cause pyroptosis and evaluated the effects of <i>Lycium barbarum</i> polysaccharides (LBP) on Aβ_1-40 oligomers-induced retinal pigment epithelium 19 (ARPE-19) damage, which is an in vitro AMD model. Aβ_1-40 oligomers verified by Western blot were added to ARPE-19 cells with or without 24 h LBP treatment. Aβ_1-40 oligomers significantly decreased ARPE-19 cell viability with obvious morphological changes under light microscopy. SEM revealed swollen cells with a bubbling appearance and ruptured cell membrane, which are morphological characteristics of pyroptosis. ELISA results showed increased expression of IL-1β and IL-18, which are the final products of pyroptosis. LBP administration for 24 h had no toxic effects on ARPE-19 cells and improved cell viability and morphology while disrupting Aβ_1-40 oligomerization in a dose-dependent manner. Furthermore, Aβ_1-40 oligomers up-regulated the cellular immunoreactivity of pyroptosis markers including NOD-like receptors protein 3 (NLRP3), caspase-1, and membrane N-terminal cleavage product of GSDMD (GSDMD-N), which could be reversed by LBP treatment. Taken together, this study showed that LBP effectively protects the Aβ_1-40 oligomers-induced pyroptotic ARPE-19 cell damages by its anti-Aβ_1-40 oligomerization properties and its anti-pyroptotic effects.