title: Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus.
abstract: The acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogenesis of Alzheimer's disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Aβ, an event that could be important during the early stages of the disease. We show that oligomerised Aβ induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSC(A)) when applied intracellularly. This effect is dependent on postsynaptic Ca(2+) and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca(2+)-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSC(A). These results suggest that a primary neuronal response to intracellular Aβ oligomers is the rapid synaptic insertion of CP-AMPARs.
authors.affiliation: 1] Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (LINE) [2] Centre for Synaptic Plasticity, Faculty of Medicine and Dentistry, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Whitcomb
authors.affiliation: 1] Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (LINE) [2] Centre for Synaptic Plasticity, Faculty of Medicine and Dentistry, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom.
authors.forename: Ellen L
authors.initials: EL
authors.lastname: Hogg
authors.affiliation: 1] Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (LINE) [2] Centre for Synaptic Plasticity, Faculty of Medicine and Dentistry, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom [3] School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Regan
authors.affiliation: 1] Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (LINE) [2] Centre for Synaptic Plasticity, Faculty of Medicine and Dentistry, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Piers
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Narayan
authors.affiliation: 1] Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (LINE) [2] Centre for Synaptic Plasticity, Faculty of Medicine and Dentistry, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom.
authors.forename: Garry
authors.initials: G
authors.lastname: Whitehead
authors.affiliation: 1] Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (LINE) [2] Centre for Synaptic Plasticity, Faculty of Medicine and Dentistry, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom [3] School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Bryony L
authors.initials: BL
authors.lastname: Winters
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (LINE).
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Center for Synaptic Brain Dysfunctions, Institute for Basic Science and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea.
authors.forename: Eunjoon
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK.
authors.forename: David
authors.initials: D
authors.lastname: Klenerman
authors.affiliation: 1] Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (LINE) [2] Centre for Synaptic Plasticity, Faculty of Medicine and Dentistry, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom [3] School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors.forename: Graham L
authors.initials: GL
authors.lastname: Collingridge
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (LINE).
authors.forename: Jihoon
authors.initials: J
authors.lastname: Jo
authors.affiliation: 1] Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (LINE) [2] Centre for Synaptic Plasticity, Faculty of Medicine and Dentistry, University of Bristol, Whitson Street, Bristol BS1 3NY, United Kingdom.
authors.forename: Kwangwook
authors.initials: K
authors.lastname: Cho
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002118:Calcium; D017868:Cyclic AMP-Dependent Protein Kinases; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; C104722:glutamate receptor ionotropic, AMPA 2