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AbstractPurpose:The study aims to assess the impact of a high-fat diet on the retinal pigment epithelium of aged TgAPPswePS1 transgenic mice, focusing on the involvement of the pyroptosis pathway.Methods:Experimental study. Comparison was made between 12 18-month-old TgAPPswePS1 transgenic mice fed with high-fat diet（experimental group）and 12 TgAPPswePS1 transgenic mice of the same background and age(contral group).The fundus was examined through Micron IV. The eyes were treated with paraffin-embedded, and mode slices. HE staining was used to observe the structure of retina and take a measurement of retinal thickness. Immunofluorescence staining was conducted to detect the amyloid-beta in retinal pigment epithelium, label the expression of retinal pigment epithelium pyrolytic related proteins NLRP3, Caspase-1, GSDMD, IL-1β and IL-18, and count the number of retinal pigment epithelium. The quantitative comparison of Aβ, retinal pigment epithelium number, retinal thickness and pyrolytic related proteins NLRP3, Caspase-1, GSDMD, IL-1β and IL-18 for experimental group and control group was statistically analyzed using t test for independent samples.Results:The retinal pigment epithelium in the experimental group showed strongly positive after stained with Aβ (P<0.0001). Compared with the control group, the thickness of retina in the experimental group was significantly reduced (t=5, P=0.0075), the number of retinal pigment epithelium was statistically decreased (t=4.243, P=0.0132), and the pyrolytic related proteins NLRP3, Caspase-1, GSDMD, IL-1β and IL-18 were strongly red positive in retinal pigment epithelium (P<0.05). Conclusion:Our findings suggest that high-fat diet leads to Aβ accumulation in the RPE of aged TgAPPswePS1 mice, potentially causing RPE damage, and the pyroptosis pathway may play a crucial role in accelerating this process.