title: 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.
authors.affiliation: Encephalopathy Therapy Area, The Affiliated Hospital of Changchun University of Chinese Medicine , Changchun Jilin, People's Republic of China .
authors.forename: Yi-dan
authors.initials: YD
authors.lastname: Zhang
authors.affiliation: Encephalopathy Therapy Area, The Affiliated Hospital of Changchun University of Chinese Medicine , Changchun Jilin, People's Republic of China .
authors.forename: Jian-jun
authors.initials: JJ
authors.lastname: Zhao
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D001522:Behavior, Animal; D002460:Cell Line; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity; D010588:Phagosomes / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D010446:Peptide Fragments; C484068:Tcfeb protein, mouse; C075222:amyloid beta-protein (1-42)