Tomatidine Ameliorates Diabetes‐Induced Cognitive Impairment and Tau Hyperphosphorylation Through the AMPK ‐ TFEB Pathway

Diabetes is associated with an increased risk of cognitive impairment. Autophagy-lysosomal dysfunction is a key feature of diabetes that contributes to dementia. Transcription factor EB (TFEB) is a master regulator of the autophagy-lysosomal function. Although the TFEB level and activity are known to be significantly decreased in transgenic mouse models of Alzheimer's disease, the role of TFEB in diabetes-associated cognitive decline remains unknown. Tomatidine protects nerve cells through reduced inflammation, oxidative stress, and cell apoptosis, which also increases the TFEB expression. In the present study, we elucidated whether tomatidine activates TFEB and ameliorates diabetes-associated cognitive impairment. The results revealed that tomatidine ameliorated diabetes-induced cognitive impairment and tau protein hyperphosphorylation through TFEB activation. Furthermore, tomatidine activated AMP-activated protein kinase (AMPK). When AMPK was inhibited, the improvement role of tomatidine disappeared. Taken together, tomatidine exerted a partial protective effect on diabetes-associated cognitive impairment by modulating the AMPK-TFEB signaling pathway.