title: Deleterious effects of soluble amyloid-β oligomers on multiple steps of synaptic vesicle trafficking.
abstract: Growing evidence supports a role for soluble amyloid-β oligomer intermediates in the synaptic dysfunction associated with Alzheimer's disease (AD), but the molecular mechanisms underlying this effect remain unclear. We found that acute treatment of cultured rat hippocampal neurons with nanomolar concentrations of Aβ oligomers reduced the recycling pool and increased the resting pool of synaptic vesicles. Endocytosis of synaptic vesicles and the regeneration of fusion-competent vesicles were also severely impaired. Furthermore, the release probability of the readily-releasable pool (RRP) was increased, and recovery of the RRP was delayed. All these effects were prevented by antibody against Aβ. Moreover reduction of the pool size was prevented by inhibiting calpain or CDK5, while the defects in endocytosis were averted by overexpressing phosphatidylinositol-4-phosphate-5-kinase type I-γ, indicating that these two downstream pathways are involved in Aβ oligomers-induced presynaptic dysfunction.
authors.affiliation: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Joohyun
authors.initials: J
authors.lastname: Park
authors.forename: Mirye
authors.initials: M
authors.lastname: Jang
authors.forename: Sunghoe
authors.initials: S
authors.lastname: Chang
mesh_terms: D016229:Amyloid beta-Peptides / Q000172:deficiency* / Q000494:pharmacology; D000818:Animals; D002154:Calpain / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004622:Embryo, Mammalian; D004705:Endocytosis / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000166:cytology; D009474:Neurons / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates; D011247:Pregnancy; D011336:Probability; D011726:Pyridinium Compounds / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C092350:FM 4-64; D018129:Phosphatidylinositol Phosphates; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; C493466:Slc17a7 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; C037178:phosphatidylinositol 4-phosphate; D051360:Cyclin-Dependent Kinase 5; D002154:Calpain