title: First effects of rising amyloid-β in transgenic mouse brain: synaptic transmission and gene expression.
abstract: Detecting and treating Alzheimer's disease, before cognitive deficits occur, has become the health challenge of our time. The earliest known event in Alzheimer's disease is rising amyloid-β. Previous studies have suggested that effects on synaptic transmission may precede plaque deposition. Here we report how relative levels of different soluble amyloid-β peptides in hippocampus, preceding plaque deposition, relate to synaptic and genomic changes. Immunoprecipitation-mass spectrometry was used to measure the early rise of different amyloid-β peptides in a mouse model of increasing amyloid-β ('TASTPM', transgenic for familial Alzheimer's disease genes APP/PSEN1). In the third postnatal week, several amyloid-β peptides were above the limit of detection, including amyloid-β40, amyloid-β38 and amyloid-β42 with an intensity ratio of 6:3:2, respectively. By 2 months amyloid-β levels had only increased by 50% and although the ratio of the different peptides remained constant, the first changes in synaptic currents, compared to wild-type mice could be detected with patch-clamp recordings. Between 2 and 4 months old, levels of amyloid-β40 rose by ∼7-fold, but amyloid-β42 rose by 25-fold, increasing the amyloid-β42:amyloid-β40 ratio to 1:1. Only at 4 months did plaque deposition become detectable and only in some mice; however, synaptic changes were evident in all hippocampal fields. These changes included increased glutamate release probability (P < 0.001, n = 7-9; consistent with the proposed physiological effect of amyloid-β) and loss of spontaneous action potential-mediated activity in the cornu ammonis 1 (CA1) and dentate gyrus regions of the hippocampus (P < 0.001, n = 7). Hence synaptic changes occur when the amyloid-β levels and amyloid-β42:amyloid-β40 ratio are still low compared to those necessary for plaque deposition. Genome-wide microarray analysis revealed changes in gene expression at 2-4 months including synaptic genes being strongly affected but often showing significant changes only by 4 months. We thus demonstrate that, in a mouse model of rising amyloid-β, the initial deposition of plaques does not occur until several months after the first amyloid-β becomes detectable but coincides with a rapid acceleration in the rise of amyloid-β levels and the amyloid-β42:amyloid-β40 ratio. Prior to acceleration, however, there is already a pronounced synaptic dysfunction, reflected as changes in synaptic transmission and altered gene expression, indicating that restoring synaptic function early in the disease progression may represent the earliest possible target for intervention in the onset of Alzheimer's disease.
authors.affiliation: 1 Department of Neuroscience, Physiology and Pharmacology, UCL, Gower St, London WC1E 6BT, UK.
authors.forename: Damian M
authors.initials: DM
authors.lastname: Cummings
authors.affiliation: 1 Department of Neuroscience, Physiology and Pharmacology, UCL, Gower St, London WC1E 6BT, UK.
authors.forename: Wenfei
authors.initials: W
authors.lastname: Liu
authors.affiliation: 2 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Portelius
authors.affiliation: 3 Hitachi Europe Ltd. European Rail Research Centre, Holborn, London, UK.
authors.forename: Sevinç
authors.initials: S
authors.lastname: Bayram
authors.affiliation: 1 Department of Neuroscience, Physiology and Pharmacology, UCL, Gower St, London WC1E 6BT, UK.
authors.forename: Marina
authors.initials: M
authors.lastname: Yasvoina
authors.affiliation: 1 Department of Neuroscience, Physiology and Pharmacology, UCL, Gower St, London WC1E 6BT, UK.
authors.forename: Sui-Hin
authors.initials: SH
authors.lastname: Ho
authors.affiliation: 1 Department of Neuroscience, Physiology and Pharmacology, UCL, Gower St, London WC1E 6BT, UK.
authors.forename: Hélène
authors.initials: H
authors.lastname: Smits
authors.affiliation: 1 Department of Neuroscience, Physiology and Pharmacology, UCL, Gower St, London WC1E 6BT, UK.
authors.forename: Shabinah S
authors.initials: SS
authors.lastname: Ali
authors.affiliation: 1 Department of Neuroscience, Physiology and Pharmacology, UCL, Gower St, London WC1E 6BT, UK.
authors.forename: Rivka
authors.initials: R
authors.lastname: Steinberg
authors.affiliation: 1 Department of Neuroscience, Physiology and Pharmacology, UCL, Gower St, London WC1E 6BT, UK.
authors.forename: Chrysia-Maria
authors.initials: CM
authors.lastname: Pegasiou
authors.affiliation: 1 Department of Neuroscience, Physiology and Pharmacology, UCL, Gower St, London WC1E 6BT, UK.
authors.forename: Owain T
authors.initials: OT
authors.lastname: James
authors.affiliation: 4 Reta Lila Research Laboratories and Department of Molecular Neuroscience, UCL, Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ, UK 5 Department of Clinical and Experimental Epilepsy, Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
authors.forename: Mar
authors.initials: M
authors.lastname: Matarin
authors.affiliation: 6 Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, SG1 2NY, UK.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Richardson
authors.affiliation: 2 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden 4 Reta Lila Research Laboratories and Department of Molecular Neuroscience, UCL, Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ, UK.
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.affiliation: 2 Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.affiliation: 4 Reta Lila Research Laboratories and Department of Molecular Neuroscience, UCL, Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ, UK.
authors.forename: John A
authors.initials: JA
authors.lastname: Hardy
authors.affiliation: 1 Department of Neuroscience, Physiology and Pharmacology, UCL, Gower St, London WC1E 6BT, UK.
authors.forename: Dervis A
authors.initials: DA
authors.lastname: Salih
authors.affiliation: 1 Department of Neuroscience, Physiology and Pharmacology, UCL, Gower St, London WC1E 6BT, UK f.a.edwards@ucl.ac.uk.
authors.forename: Frances A
authors.initials: FA
authors.lastname: Edwards
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D018408:Patch-Clamp Techniques; D058225:Plaque, Amyloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009435:Synaptic Transmission / Q000502:physiology*; D059467:Transcriptome
chemical_list: D016229:Amyloid beta-Peptides
keywords: Alzheimer’s disease; amyloid; gene expression; mouse; synaptic transmission