title: Type-1 interferon signaling mediates neuro-inflammatory events in models of Alzheimer's disease.
abstract: A neuro-inflammatory response has been implicated in human patients and animal models of Alzheimer's disease (AD). Type-1 interferons are pleiotropic cytokines involved in the initiation and regulation of the pro-inflammatory response; however, their role in AD is unknown. This study investigated the contribution of type-1 IFN signaling in the neuro-inflammatory response to amyloid-beta (Aβ) in vitro and in the APP/PS1 transgenic mouse model of AD. Enzyme-linked immunosorbent assay confirmed a 2-fold increase in IFNα in APP/PS1 brains compared with control brains. Quantitative polymerase chain reaction also identified increased IFNα and IFNβ expression in human pre-frontal cortex from AD patients. In vitro studies in primary neurons demonstrated Aβ-induced type-1 IFN expression preceded that of other classical pro-inflammatory cytokines, IL1-β, and IL-6. Significantly, ablation of type-1 interferon-α receptor 1 expression in BE(2)M17 neuroblastoma cells and primary neurons afforded protection against Aβ-induced toxicity. This study supports a role for type-1 interferons in the pro-inflammatory response and neuronal cell death in AD and suggests that blocking type-1 interferon-α receptor 1 maybe a therapeutic target to limit the disease progression.
authors.affiliation: Department of Pharmacology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Juliet M
authors.initials: JM
authors.lastname: Taylor
authors.affiliation: Department of Pharmacology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Myles R
authors.initials: MR
authors.lastname: Minter
authors.affiliation: Department of Pharmacology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Newman
authors.affiliation: Department of Pharmacology, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Moses
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Synaptic Neurobiology Laboratory, Mental Health Research Institute, Melbourne, Victoria, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Adlard
authors.affiliation: Department of Pharmacology, University of Melbourne, Melbourne, Victoria, Australia. Electronic address: pcrack@unimelb.edu.au.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crack
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D007370:Interferon Type I / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta
keywords: Alzheimer's disease; Interleukin-1β; Interleukin-6; JAK-Stat; Neuro-inflammation; Type-1 interferons