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

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 (GSK3 beta)-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-GSK3 beta serine9 (p-GSK3 beta ser9), TFEB and transient receptor potential mucolipin 1, ADAM10, oligosaccharyl transferase-48, estrogen receptor alpha and induces TFEB nuclear translocation in hippocampus, elevates IDE and ER beta in cortex, while reduces p-tau ser396&404, CDK5, cathepsin B, and glial fibrillary acidic protein in hippocampus. Trehalose elevates p-GSK3 beta 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 ER beta. Trehalose can strongly reverse dAGEs-induced tau phosphorylation by potentiating TFEB nuclear translocation via inhibiting GSK-3 beta.

Automated summary

This study demonstrates that dietary advanced glycation end products (dAGEs) impair cognitive function only in female mice, and trehalose can protect neurofunction by modulating the glycogen synthase kinase-3 beta (GSK3 beta)-transcription factor EB (TFEB) signaling pathway.