title: TL-2 attenuates β-amyloid induced neuronal apoptosis through the AKT/GSK-3β/β-catenin pathway.
abstract: β-amyloid (Aβ)-mediated neuronal apoptosis contributes to the progression of Alzheimer's disease (AD), although the exact mechanism remains unclear. This study aimed to investigate whether Dalesconol B (TL-2), a potent immunosuppressive agent with an unusual carbon skeleton, could inhibit Aβ-induced apoptosis in vitro and in vivo and to explore the underlying mechanisms. Aβ(1-42) was injected to bilateral hippocampus of mice to make the AD models in vivo. TL-2 was able to cross the blood-brain barrier and attenuate memory deficits in the AD mice. TL-2 also inhibited Aβ(1-42)-induced neuronal apoptosis in vitro and in vivo. In addition, TL-2 could activate the AKT/GSK-3β pathway, and inhibition of AKT and activation of GSK-3β partially eliminated the neuroprotective effects of TL-2. Furthermore, TL-2 induced the nuclear translocation of β-catenin and enhanced its transcriptional activity through the AKT/GSK-3β pathway to promote neuronal survival. These results suggest that TL-2 might be a potential drug for AD treatment.
authors.affiliation: Department of Neurology,Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing,PR China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine,Nanjing University of Chinese Medicine,Nanjing,PR China.
authors.forename: Sulei
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Neurology,Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing,PR China.
authors.forename: Linjie
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine,Nanjing University of Chinese Medicine,Nanjing,PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules,Nanjing University,Nanjing,PR China.
authors.forename: Renxiang
authors.initials: R
authors.lastname: Tan
authors.affiliation: Department of Neurology,Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing,PR China.
authors.forename: Kailin
authors.initials: K
authors.lastname: Yin
authors.affiliation: Department of Neurology,Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing,PR China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Neurology,Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing,PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Neurology,Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing,PR China.
authors.forename: Dening
authors.initials: D
authors.lastname: Guan
authors.affiliation: Department of Neurology,Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing,PR China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000473:pathology; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity; D011084:Polycyclic Aromatic Hydrocarbons / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011084:Polycyclic Aromatic Hydrocarbons; C075222:amyloid beta-protein (1-42); D051176:beta Catenin; C552721:dalesconol B; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D053453:Caspase 9