TFEB Participates in the Aβ-Induced Pathogenesis of Alzheimer's Disease by Regulating the Autophagy-Lysosome Pathway.

Abstract

To investigate whether transcriptional factor EB (TFEB) participates in amyloid-β(1-42) (Aβ(1-42))-induced pathogenesis of Alzheimer's disease (AD) and its underlying mechanisms. Three-month-old and 8-month-old transgenic APP/PS1 AD mice and age-matched wild mice were used in this study. We found that the 8-month-old AD animals presented significantly higher deposition of Aβ(1-42) and expression of TFEB and its targeted proteins, such as LAMP-1 and cathepsin D, and autophagy-associated LC3-II and p62 in brain tissues than in others. In an in vitro study, TFEB overexpression rescued autophagic flux that blocked by Aβ(1-42) and the degradation of the absorbed Aβ(1-42), relieved Aβ(1-42)-mediated induction of overloaded autophagy. In addition, TFEB overexpression enhanced cathepsin D expression and activity, restored Aβ(1-42)-disturbed acid environment of lysosome, and promoted the fusion of autophagosomes with lysosomes. Furthermore, TFEB upregulation reduced Aβ(1-42)-induced production of malondialdehyde, oxidative carbonyl proteins, and reactive oxygen species (ROS) and cell apoptosis mainly dependent on the removal of Aβ(1-42) by the autophagy-lysosome pathway. TFEB overexpression alleviated AD progression by reducing Aβ accumulation through regulating the autophagy-lysosome pathway and reducing Aβ-induced ROS production and cell apoptosis.