title: Differential deregulation of astrocytic calcium signalling by amyloid-β, TNFα, IL-1β and LPS.
abstract: In Alzheimer's disease (AD), astrocytes undergo complex morphological and functional changes that include early atrophy, reactive activation and Ca(2+) deregulation. Recently, we proposed a mechanism by which nanomolar Aβ42 deregulates mGluR5 and InsP3 receptors, the key elements of astrocytic Ca(2+) signalling toolkit. To evaluate the specificity of these changes, we have now investigated whether the effects of Aβ42 on Ca(2+) signalling machinery can be reproduced by pro-inflammatory agents (TNFα, IL-1β, LPS). Here we report that Aβ42 (100nM, 72h) significantly increased mRNA levels of mGluR5, InsP3R1 and InsP3R2, whereas pro-inflammatory agents reduced expression of these specific mRNAs. Furthermore, DHPG-induced Ca(2+) signals and store operated Ca(2+) entry (SOCE) were augmented in Aβ42-treated cells due to up-regulation of a set of Ca(2+) signalling-related genes including TRPC1 and TRPC4. Opposite changes were observed when astrocytes were treated with TNFα, IL-1β and LPS. Last, the effects observed on SOCE by treating wild-type astrocytes with Aβ42 were also identified in untreated astrocytes from 3×Tg-AD animals, suggesting a link to the AD pathology. Our results demonstrate that effects of Aβ42 on astrocytic Ca(2+) signalling differ from and may contrast to the effects of pro-inflammatory agents.
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale "Amedeo Avogadro", 28100 Novara, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ronco
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale "Amedeo Avogadro", 28100 Novara, Italy.
authors.forename: Ambra A
authors.initials: AA
authors.lastname: Grolla
authors.affiliation: Christian Doppler Laboratory for Flow Chemistry (CDLFC), Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria.
authors.forename: Toma N
authors.initials: TN
authors.lastname: Glasnov
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale "Amedeo Avogadro", 28100 Novara, Italy.
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Canonico
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester M13 9PL, UK; IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain; Department of Neurosciences, University of the Basque Country UPV/EHU and CIBERNED, 48940 Leioa, Spain.
authors.forename: Alexei
authors.initials: A
authors.lastname: Verkhratsky
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale "Amedeo Avogadro", 28100 Novara, Italy. Electronic address: armando.genazzani@pharm.unipmn.it.
authors.forename: Armando A
authors.initials: AA
authors.lastname: Genazzani
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale "Amedeo Avogadro", 28100 Novara, Italy.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Lim
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002478:Cells, Cultured; D020672:I-kappa B Proteins / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D010446:Peptide Fragments / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D020672:I-kappa B Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C000606206:Nfkbia protein, rat; D010446:Peptide Fragments; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); C096351:transient receptor potential cation channel, subfamily C, member 1; D000072000:NF-KappaB Inhibitor alpha; D008734:Methoxyhydroxyphenylglycol; D002118:Calcium; C010117:3,4-dihydroxyphenylglycol
keywords: Alzheimer disease; Astrocytes; Ca(2+) signalling; Ca(2+) stores; Cytokines; Store-operated Ca(2+) entry; β-Amyloid