title: Inhibition of the Motor Protein Eg5/Kinesin-5 in Amyloid β-Mediated Impairment of Hippocampal Long-Term Potentiation and Dendritic Spine Loss.
abstract: Alzheimer's disease (AD) is characterized by neurofibrillary tangles, amyloid plaques, and neurodegeneration. However, this pathology is preceded by increased soluble amyloid beta (Aβ) 1-42 oligomers that interfere with the glutamatergic synaptic plasticity required for learning and memory, includingN-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP). In particular, soluble Aβ(1-42) acutely inhibits LTP and chronically causes synapse loss. Many mechanisms have been proposed for Aβ-induced synaptic dysfunction, but we recently found that Aβ(1-42) inhibits the microtubule motor protein Eg5/kinesin-5. Here we compared the impacts of Aβ(1-42) and monastrol, a small-molecule Eg5 inhibitor, on LTP in hippocampal slices and synapse loss in neuronal cultures. Acute (20-minute) treatment with monastrol, like Aβ, completely inhibited LTP at doses >100 nM. In addition, 1 nM Aβ(1-42) or 50 nM monastrol inhibited LTP #x223c;50%, and when applied together caused complete LTP inhibition. At concentrations that impaired LTP, neither Aβ(1-42) nor monastrol inhibited NMDAR synaptic responses until #x223c;60 minutes, when only #x223c;25% inhibition was seen for monastrol, indicating that NMDAR inhibition was not responsible for LTP inhibition by either agent when applied for only 20 minutes. Finally, 48 hours of treatment with either 0.5-1.0μM Aβ(1-42) or 1-5μM monastrol reduced the dendritic spine/synapse density in hippocampal cultures up to a maximum of #x223c;40%, and when applied together at maximal concentrations, no additional spine loss resulted. Thus, monastrol can mimic and in some cases occlude the impact of Aβon LTP and synapse loss, suggesting that Aβinduces acute and chronic synaptic dysfunction in part through inhibiting Eg5.
authors.affiliation: Department of Pharmacology (R.K.F., E.S.G., M.L.D.'A.), and Department Neurology (H.P.), School of Medicine, and Linda Crnic Institute for Down Syndrome (M.L.D.'A., H.P.), Anschutz Medical Campus, University of Colorado, Aurora, Colorado ron.freund@ucdenver.edu mark.dellacqua@ucdenver.edu.
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Freund
authors.affiliation: Department of Pharmacology (R.K.F., E.S.G., M.L.D.'A.), and Department Neurology (H.P.), School of Medicine, and Linda Crnic Institute for Down Syndrome (M.L.D.'A., H.P.), Anschutz Medical Campus, University of Colorado, Aurora, Colorado.
authors.forename: Emily S
authors.initials: ES
authors.lastname: Gibson
authors.affiliation: Department of Pharmacology (R.K.F., E.S.G., M.L.D.'A.), and Department Neurology (H.P.), School of Medicine, and Linda Crnic Institute for Down Syndrome (M.L.D.'A., H.P.), Anschutz Medical Campus, University of Colorado, Aurora, Colorado.
authors.forename: Huntington
authors.initials: H
authors.lastname: Potter
authors.affiliation: Department of Pharmacology (R.K.F., E.S.G., M.L.D.'A.), and Department Neurology (H.P.), School of Medicine, and Linda Crnic Institute for Down Syndrome (M.L.D.'A., H.P.), Anschutz Medical Campus, University of Colorado, Aurora, Colorado ron.freund@ucdenver.edu mark.dellacqua@ucdenver.edu.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dell'Acqua
mesh_terms: D000682:Amyloid / Q000187:drug effects* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007700:Kinetics; D017774:Long-Term Potentiation / Q000187:drug effects; D036881:Long-Term Synaptic Depression / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D011743:Pyrimidines / Q000633:toxicity; D013871:Thiones / Q000633:toxicity
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011743:Pyrimidines; D013871:Thiones; C075222:amyloid beta-protein (1-42); C400223:monastrol; C521052:Kif11 protein, mouse; D016547:Kinesins