title: Induction of autophagy by a novel small molecule improves aβ pathology and ameliorates cognitive deficits.
abstract: Growing evidence has demonstrated a neuroprotective role of autophagy in Alzheimer's disease (AD). Thus, autophagy has been regarded as a potential therapeutic target, attracting increasing interest in pharmaceutical autophagy modulation by small molecules. We designed a two-cycle screening strategy on the basis of imaging high-throughout screening (HTS) and cellular toxicity assay, and have identified a novel autophagy inducer known as GTM-1. We further showed that GTM-1 exhibits dual activities, such as autophagy induction and antagonism against Aβ-oligomer toxicity. GTM-1 modulates autophagy in an Akt-independent and mTOR-independent manner. In addition, we demonstrated that GTM-1 enhances autophagy clearance and reverses the downregulation of autophagy flux by thapsigargin and asparagine. Furthermore, administration of GTM-1 attenuated Aβ pathology and ameliorated cognitive deficits in AD mice.
authors.affiliation: Department of Neurology, The First People's Hospital of Yangzhou, Jiang Su, PR China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chu
authors.forename: Xinjiang
authors.initials: X
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Ma
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Lu
authors.initials: L
authors.lastname: Shang
authors.forename: Peng
authors.initials: P
authors.lastname: Fu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D003071:Cognition / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008568:Memory / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry* / Q000633:toxicity*; D055503:Protein Multimerization / Q000187:drug effects; D017433:Protein Structure, Secondary; D011799:Quinazolines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D054852:Small Molecule Libraries / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; C000589446:GTM-1 compound; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011799:Quinazolines; D054852:Small Molecule Libraries; C075222:amyloid beta-protein (1-42)