ABSTRACT
Autophagy impairment is a key factor in Alzheimer's disease (AD) pathogenesis. TFEB (transcription factor EB) and TFE3 (transcription factor binding to IGHM enhancer 3) are nuclear transcription factors that regulate autophagy and lysosomal biogenesis. We previously showed that corynoxine (Cory), a Chinese medicine compound, protects neurons from Parkinson's disease (PD) by activating autophagy. In this study, we investigated the effect of Cory on AD models in vivo and in vitro. We found that Cory improved learning and memory function, increased neuronal autophagy and lysosomal biogenesis, and reduced pathogenic APP-CTFs levels in 5xFAD mice model. Cory activated TFEB/TFE3 by inhibiting AKT/mTOR signaling and stimulating lysosomal calcium release via transient receptor potential mucolipin 1 (TRPML1). Moreover, we demonstrated that TFEB/TFE3 knockdown abolished Cory-induced APP-CTFs degradation in N2aSwedAPP cells. Our findings suggest that Cory promotes TFEB/TFE3-mediated autophagy and alleviates Aß pathology in AD models.
Subject(s)
Alzheimer Disease , Autophagy , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Disease Models, Animal , Transient Receptor Potential Channels , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Animals , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Autophagy/drug effects , Mice , Lysosomes/metabolism , Lysosomes/drug effects , Humans , Mice, Transgenic , Amyloid beta-Peptides/metabolism , Mice, Inbred C57BL , TOR Serine-Threonine Kinases/metabolism , Male , Proto-Oncogene Proteins c-akt/metabolism , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Signal Transduction/drug effects , Amyloid beta-Protein Precursor/metabolism , Amyloid beta-Protein Precursor/geneticsABSTRACT
Dynamic mechanical properties of cells are becoming recognized as indicators and regulators of physiological processes such as differentiation, malignant phenotypes and mitosis. A key process in development and homeostasis is apoptosis and whilst the molecular control over this pathway is well studied, little is known about the mechanical consequences of cell death. Here, we study the caspase-dependent mechanical kinetics of single cells during early apoptosis initiated with the general protein-kinase inhibitor staurosporine. This results in internal remodelling of the cytoskeleton and nucleus which is reflected in dynamic changes in the mechanical properties of the cell. Utilizing simultaneous confocal and atomic force microscopy (AFM), we measured distinct mechanical dynamics in the instantaneous cellular Young's Modulus and longer timescale viscous deformation. This allowed us to visualize time-dependent nuclear and cytoskeletal control of force dissipation with fluorescent fusion proteins throughout the cell. This work reveals that the cell death program not only orchestrates biochemical dynamics but also controls the mechanical breakdown of the cell. Importantly, the consequences of mechanical disregulation during apoptosis may be a contributing factor to several human pathologies through the poorly timed release of dead cells and cell debris.