title: Examination of potential mechanisms of amyloid-induced defects in neuronal transport.
abstract: Microtubule-based neuronal transport pathways are impaired during the progression of Alzheimer's disease and other neurodegenerative conditions. However, mechanisms leading to defects in transport remain to be determined. We quantified morphological changes in neuronal cells following treatment with fibrils and unaggregated peptides of beta-amyloid (Abeta). Abeta fibrils induce axonal and dendritic swellings indicative of impaired transport. In contrast, Abeta peptides induce a necrotic phenotype in both neurons and non-neuronal cells. We tested several popular hypotheses by which aggregated Abeta could disrupt transport. Using fluorescent polystyrene beads, we developed experimental models of physical blockage and localized release of reactive oxygen species (ROS) that reliably induce swellings. Like the beads, Abeta fibrils localize in close proximity to swellings; however, fibril internalization is not required for disrupting transport. ROS and membrane permeability are also unlikely to be responsible for fibril-mediated toxicity. Collectively, our results indicate that multiple initiating factors converge upon pathways of defective transport.
authors.affiliation: Fischell Department of Bioengineering, University of Maryland, College Park, MD, USA.
authors.forename: Sameer B
authors.initials: SB
authors.lastname: Shah
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Nolan
authors.forename: Emily
authors.initials: E
authors.lastname: Davis
authors.forename: Gorazd B
authors.initials: GB
authors.lastname: Stokin
authors.forename: Ingrid
authors.initials: I
authors.lastname: Niesman
authors.forename: Isabel
authors.initials: I
authors.lastname: Canto
authors.forename: Charles
authors.initials: C
authors.lastname: Glabe
authors.forename: Lawrence S B
authors.initials: LS
authors.lastname: Goldstein
mesh_terms: D000682:Amyloid / Q000633:toxicity*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003563:Cyclic CMP / Q000031:analogs & derivatives / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D006624:Hippocampus / Q000166:cytology; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008863:Microspheres; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity; D011137:Polystyrenes; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection / Q000379:methods; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D008164:Luminescent Proteins; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D016900:Neurofilament Proteins; D010446:Peptide Fragments; D011137:Polystyrenes; D017382:Reactive Oxygen Species; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C051774:neurofilament protein H; D003563:Cyclic CMP; C053441:dibutyryl cyclic-3',5'-cytidine monophosphate; D002118:Calcium