High fat and high cholesterol diet induced cognitive impairment in GSDMD knockout mice via the compensatory activation of apoptosis pathway

Via the GSDMD knockout (KO) mice as model, we aimed to determine the roles of GSDMD-mediated pyroptosis and its crosstalk with apoptosis in regulating high fat high cholesterol (HFHC) diet associated cognitive dysfunction. Wild type (WT) and GSDMD KO mice were divided into 4 groups, i.e. WT control (WTCON), WT fed with HFHC (WTHFHC), GSDMD KO control (KOCON), GSDMD KO HFHC (KOHFHC). Compared to the KOCON group, mice from the KOHFHC group demonstrated the worst learning and memory disabilities. In the hippocampus, p-Tau ser404, RIPK1/RIP, cleaved caspase-3 and apoptosis rate were increased, while BDNF and p-CREB were reduced from the KOHFHC group. In the cortex, p-Tau ser404, p-Tau ser396, RIPK1/RIP, cleaved caspase-8 and cleaved caspase-3 were significantly increased, while BDNF, synaptophysin were reduced from KOHFHC group. RNA sequencing analysis showed that 2 pathways closely related to apoptosis were significantly upregulated from KOHFHC group compared to KOCON group, including apoptosis and positive regulation of execution phase of apoptosis. The combination of palmitic acid with LDC7559 further increased the number of apoptotic cells and cleaved caspase-3 protein expression compared to vehicle in BV2 cells and HT22 cells. In conclusion, knocking out GSDMD gene in mice had no notable effects on learning and memory abilities under normal diet, but notably led to cognitive dysfunction when stimulated by a high-fat and high-cholesterol diet. The inhibition of pyroptosis may unexpectedly compensate for the activation of exogenous apoptotic pathways, this might be associated with worsening of tau phosphorylation, synaptic plasticity, and neuroinflammation.