title: Alzheimer amyloid beta inhibition of Eg5/kinesin 5 reduces neurotrophin and/or transmitter receptor function.
abstract: The mechanism by which amyloid beta (Aβ) causes neuronal dysfunction and/or death in Alzheimer's disease (AD) is unclear. Previously, we showed that Aβ inhibits several microtubule-dependent kinesin motors essential for mitosis and also present in mature neurons. Here, we show that inhibition of kinesin 5 (Eg5) by Aβ blocks neuronal function by reducing transport of neurotrophin and neurotransmitter receptors to the cell surface. Specifically, cell-surface NGF/NTR(p75) and NMDA receptors decline in cells treated with Aβ or the kinesin 5 inhibitor monastrol, or expressing APP. Aβ and monastrol also inhibit NGF-dependent neurite outgrowth from PC12 cells and glutamate-dependent Ca++ entry into primary neurons. Like Aβ, monastrol inhibits long-term potentiation, a cellular model of NMDA-dependent learning and memory, and kinesin 5 activity is absent from APP/PS transgenic mice brain or neurons treated with Aβ. These data imply that cognitive deficits in AD may derive in part from inhibition of neuronal Eg5 by Aβ, resulting in impaired neuronal function and/or survival through receptor mislocalization. Preventing inhibition of Eg5 or other motors by Aβ may represent a novel approach to AD therapy.
authors.affiliation: USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA; Department of Molecular Medicine, College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Csilla
authors.initials: C
authors.lastname: Ari
authors.affiliation: USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA; Department of Molecular Medicine, College of Medicine, University of South Florida, Tampa, FL, USA; Eric Pfeiffer Suncoast Alzheimer's Center, University of South Florida, Tampa, FL, USA; Department of Oncology, H. Lee Moffitt Cancer and Research Center, Tampa, FL, USA.
authors.forename: Sergiy I
authors.initials: SI
authors.lastname: Borysov
authors.affiliation: Department of Molecular Pharmacology and Physiology, College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Jiashin
authors.initials: J
authors.lastname: Wu
authors.affiliation: USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA; Department of Molecular Medicine, College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Jaya
authors.initials: J
authors.lastname: Padmanabhan
authors.affiliation: USF Health Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA; Department of Molecular Medicine, College of Medicine, University of South Florida, Tampa, FL, USA; Eric Pfeiffer Suncoast Alzheimer's Center, University of South Florida, Tampa, FL, USA; Department of Neurology and Linda Crnic Institute for Down Syndrome, Anschutz Medical Campus, University of Colorado, Denver, Aurora, CO, USA. Electronic address: Huntington.Potter@UCDenver.edu.
authors.forename: Huntington
authors.initials: H
authors.lastname: Potter
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000009:adverse effects* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003071:Cognition; D005260:Female; D018698:Glutamic Acid / Q000502:physiology; D016547:Kinesins / Q000037:antagonists & inhibitors*; D017774:Long-Term Potentiation / Q000187:drug effects; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D020932:Nerve Growth Factor / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D016501:Neurites / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects; D016716:PC12 Cells; D011247:Pregnancy; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D013871:Thiones / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D009414:Nerve Growth Factors; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D013871:Thiones; D018698:Glutamic Acid; C400223:monastrol; D020932:Nerve Growth Factor; C521052:Kif11 protein, mouse; D016547:Kinesins; D002118:Calcium
keywords: Abeta peptide; Alzheimer's disease; Down syndrome; Eg5; Kinesin 5; Microtubules; NMDA receptor; Neurite outgrowth; Neurodegeneration; Neurotransmitter receptor; Neurotrophin receptor; p75