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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alzheimer Disease* / chemically induced
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Alzheimer Disease* / complications
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Alzheimer Disease* / drug therapy
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Alzheimer Disease* / pathology
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Amyloid beta-Peptides / toxicity
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Animals
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Apoptosis / drug effects*
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Caspase 3 / metabolism
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Caspase 9 / metabolism
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Cells, Cultured
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Cerebral Cortex / cytology
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Cerebral Cortex / pathology
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Chromones / pharmacology
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Disease Models, Animal
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Enzyme Inhibitors / pharmacology
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Maze Learning / drug effects
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Memory Disorders / chemically induced
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Memory Disorders / drug therapy
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Mice
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Morpholines / pharmacology
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Neurons / drug effects*
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Neuroprotective Agents / therapeutic use*
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Oncogene Protein v-akt / metabolism
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Peptide Fragments / toxicity
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Polycyclic Aromatic Hydrocarbons / therapeutic use*
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Signal Transduction / drug effects*
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beta Catenin / metabolism
Substances
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Amyloid beta-Peptides
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Chromones
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Enzyme Inhibitors
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Morpholines
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Neuroprotective Agents
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Peptide Fragments
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Polycyclic Aromatic Hydrocarbons
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amyloid beta-protein (1-42)
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beta Catenin
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dalesconol B
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Oncogene Protein v-akt
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Glycogen Synthase Kinase 3
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Caspase 3
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Caspase 9