Sex‐Specific Neurotoxicity of Dietary Advanced Glycation End Products in APP/PS1 Mice and Protective Roles of Trehalose by Inhibiting Tau Phosphorylation via GSK‐3β‐TFEB
Huanhuan Zhou, Lan Luo, Xuedi Zhai, Liangkai Chen, Guiping Wang, Li‐Qiang Qin, Zengli Yu, Lili Xin, Zhongxiao Wan
Abstract
SCOPE: It remains unclear whether dietary advanced glycation end products (dAGEs)-induced cognitive impairment is sex-dependent. Trehalose may antagonize dAGEs-induced neurotoxicity via glycogen synthase kinase-3 beta (GSK3β)-transcription factor EB (TFEB) signaling. METHODS AND RESULTS: The sex-specific neurotoxicity of dAGEs and the protective role of trehalose are investigated both in vivo and in vitro. Both sexes of APP/PS1 mice are divided into three groups: that is, control, dAGEs, and dAGEs supplemented with trehalose. SHSY-5Y cells incubated with AGE-BSA and trehalose are also utilized. Dietary AGEs impair cognitive function only in female mice, which is restored by trehalose. Trehalose upregulates phosphorylated-GSK3β serine9 (p-GSK3β ser9), TFEB and transient receptor potential mucolipin 1, ADAM10, oligosaccharyl transferase-48, estrogen receptor α and induces TFEB nuclear translocation in hippocampus, elevates IDE and ERβ in cortex, while reduces p-tau ser396&404, CDK5, cathepsin B, and glial fibrillary acidic protein in hippocampus. Trehalose elevates p-GSK3β ser9, induces TFEB nuclear translocation, consequently reverses AGE-BSA-induced tau phosphorylation in vitro. CONCLUSIONS: Female mice are more susceptible to the deleterious effects of dAGEs on cognitive function, which may be owing to its regulation on ERβ. Trehalose can strongly reverse dAGEs-induced tau phosphorylation by potentiating TFEB nuclear translocation via inhibiting GSK-3β.