TRIM16-mediated lysophagy suppresses high-glucose-accumulated neuronal A & beta;

Lysosomal dysfunction is a pathogenic link that may explain the causal relationship between diabetes and Alzheimer disease; however, there is no information about the regulation of hyperglycemia in neuronal lysophagy modulating lysosomal function. We examined the effect and related mechanisms of action of high glucose on lysophagy impairment and subsequent A beta accumulation in human induced pluripotent stem cell (hiPSC)-derived neurons, mouse hippocampal neurons, and streptozotocin (STZ)-induced diabetic mice. High-glucose induced neuronal lysosomal dysfunction through reactive oxygen species-mediated lysosomal membrane permeabilization and lysophagy impairment. Among lysophagy-related factors, the expression of TRIM16 (tripartite motif containing 16) was reduced in high-glucose-treated neuronal cells and the diabetic hippocampus through MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1)-mediated inhibition of TFEB (transcription factor EB) activity. TRIM16 overexpression recovered lysophagy through the recruitment of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3), SQSTM1/p62, and ubiquitin to damaged lysosomes, which inhibited the high-glucose-induced accumulation of A beta and p-MAPT/tau. In the diabetic mice model, TFEB enhancer recovered lysophagy in the hippocampus, resulting in the amelioration of cognitive impairment. In conclusion, TRIM16-mediated lysophagy is a promising candidate for the inhibition of diabetes-associated Alzheimer disease pathogenesis.

Automated summary

Lysosomal dysfunction caused by high glucose leads to the accumulation of A beta and p-MAPT/tau, which may contribute to the pathogenesis of diabetes-associated Alzheimer's disease. TRIM16 restores lysophagy and inhibits the accumulation of A beta and p-MAPT/tau induced by high glucose, providing a potential target for inhibiting the development of diabetes-associated Alzheimer's disease.