title: Amyloid-β oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons.
abstract: Disruption of fast axonal transport (FAT) is an early pathological event in Alzheimer's disease (AD). Soluble amyloid-β oligomers (AβOs), increasingly recognized as proximal neurotoxins in AD, impair organelle transport in cultured neurons and transgenic mouse models. AβOs also stimulate hyperphosphorylation of the axonal microtubule-associated protein, tau. However, the role of tau in FAT disruption is controversial. Here we show that AβOs reduce vesicular transport of brain-derived neurotrophic factor (BDNF) in hippocampal neurons from both wild-type and tau-knockout mice, indicating that tau is not required for transport disruption. FAT inhibition is not accompanied by microtubule destabilization or neuronal death. Significantly, inhibition of calcineurin (CaN), a calcium-dependent phosphatase implicated in AD pathogenesis, rescues BDNF transport. Moreover, inhibition of protein phosphatase 1 and glycogen synthase kinase 3β, downstream targets of CaN, prevents BDNF transport defects induced by AβOs. We further show that AβOs induce CaN activation through nonexcitotoxic calcium signaling. Results implicate CaN in FAT regulation and demonstrate that tau is not required for AβO-induced BDNF transport disruption.
authors.affiliation: Department of Biological Sciences, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
authors.forename: Elisa M
authors.initials: EM
authors.lastname: Ramser
authors.forename: Kathlyn J
authors.initials: KJ
authors.lastname: Gan
authors.forename: Helena
authors.initials: H
authors.lastname: Decker
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Fan
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Suzuki
authors.forename: Sergio T
authors.initials: ST
authors.lastname: Ferreira
authors.forename: Michael A
authors.initials: MA
authors.lastname: Silverman
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D001692:Biological Transport; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D019703:Calcineurin / Q000187:drug effects / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D020013:Calcium Signaling; D002478:Cells, Cultured; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D016559:Tacrolimus / Q000494:pharmacology; D014404:Tubulin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; C558298:Mapt protein, mouse; D014404:Tubulin; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin; D054645:Protein Phosphatase 1; D016559:Tacrolimus