title: Opposing synaptic regulation of amyloid-β metabolism by NMDA receptors in vivo.
abstract: The concentration of amyloid-β (Aβ) within the brain extracellular space is one determinant of whether the peptide will aggregate into toxic species that are important in Alzheimer's disease (AD) pathogenesis. Some types of synaptic activity can regulate Aβ levels. Here we demonstrate two distinct mechanisms that are simultaneously activated by NMDA receptors and regulate brain interstitial fluid (ISF) Aβ levels in opposite directions in the living mouse. Depending on the dose of NMDA administered locally to the brain, ISF Aβ levels either increase or decrease. Low doses of NMDA increase action potentials and synaptic transmission which leads to an elevation in synaptic Aβ generation. In contrast, high doses of NMDA activate signaling pathways that lead to ERK (extracellular-regulated kinase) activation, which reduces processing of APP into Aβ. This depression in Aβ via APP processing occurs despite dramatically elevated synaptic activity. Both of these synaptic mechanisms are simultaneously active, with the balance between them determining whether ISF Aβ levels will increase or decrease. NMDA receptor antagonists increase ISF Aβ levels, suggesting that basal activity at these receptors normally suppresses Aβ levels in vivo. This has implications for understanding normal Aβ metabolism as well as AD pathogenesis.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Verges
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Restivo
authors.forename: Whitney D
authors.initials: WD
authors.lastname: Goebel
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D058256:Brain Waves / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004569:Electroencephalography / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D047309:Flavones / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D016202:N-Methylaspartate / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D047309:Flavones; C508853:PSEN1 protein, human; D010879:Piperazines; D010880:Piperidines; D053764:Presenilin-1; D016194:Receptors, N-Methyl-D-Aspartate; D026941:Sodium Channel Blockers; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D012701:Serotonin; D013779:Tetrodotoxin; D004533:Egtazic Acid; D016202:N-Methylaspartate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D011280:Pregnanolone; D048049:Extracellular Signal-Regulated MAP Kinases; C010739:ifenprodil; D002118:Calcium