PU.1 regulates Alzheimer's disease-associated genes in primary human microglia.

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dc.contributor.author Rustenhoven, Justin en
dc.contributor.author Smith, Amy M en
dc.contributor.author Smyth, Leon en
dc.contributor.author Jansson, Deidre en
dc.contributor.author Scotter, Emma en
dc.contributor.author Swanson, Molly en
dc.contributor.author Aalderink, Miranda en
dc.contributor.author Coppieters 't Wallant, Natacha en
dc.contributor.author Narayan, Pritika en
dc.contributor.author Handley, Renee en
dc.contributor.author Overall, Chris en
dc.contributor.author Park, In en
dc.contributor.author Schweder, Patrick en
dc.contributor.author Heppner, Peter en
dc.contributor.author Curtis, Maurice en
dc.contributor.author Faull, Richard en
dc.contributor.author Dragunow, Michael en
dc.date.accessioned 2019-09-29T22:00:03Z en
dc.date.issued 2018-08-20 en
dc.identifier.citation Molecular neurodegeneration 13(1):44 20 Aug 2018 en
dc.identifier.issn 1750-1326 en
dc.identifier.uri http://hdl.handle.net/2292/47996 en
dc.description.abstract BACKGROUND:Microglia play critical roles in the brain during homeostasis and pathological conditions. Understanding the molecular events underpinning microglial functions and activation states will further enable us to target these cells for the treatment of neurological disorders. The transcription factor PU.1 is critical in the development of myeloid cells and a major regulator of microglial gene expression. In the brain, PU.1 is specifically expressed in microglia and recent evidence from genome-wide association studies suggests that reductions in PU.1 contribute to a delayed onset of Alzheimer's disease (AD), possibly through limiting neuroinflammatory responses. METHODS:To investigate how PU.1 contributes to immune activation in human microglia, microarray analysis was performed on primary human mixed glial cultures subjected to siRNA-mediated knockdown of PU.1. Microarray hits were confirmed by qRT-PCR and immunocytochemistry in both mixed glial cultures and isolated microglia following PU.1 knockdown. To identify attenuators of PU.1 expression in microglia, high throughput drug screening was undertaken using a compound library containing FDA-approved drugs. NanoString and immunohistochemistry was utilised to investigate the expression of PU.1 itself and PU.1-regulated mediators in primary human brain tissue derived from neurologically normal and clinically and pathologically confirmed cases of AD. RESULTS:Bioinformatic analysis of gene expression upon PU.1 silencing in mixed glial cultures revealed a network of modified AD-associated microglial genes involved in the innate and adaptive immune systems, particularly those involved in antigen presentation and phagocytosis. These gene changes were confirmed using isolated microglial cultures. Utilising high throughput screening of FDA-approved compounds in mixed glial cultures we identified the histone deacetylase inhibitor vorinostat as an effective attenuator of PU.1 expression in human microglia. Further characterisation of vorinostat in isolated microglial cultures revealed gene and protein changes partially recapitulating those seen following siRNA-mediated PU.1 knockdown. Lastly, we demonstrate that several of these PU.1-regulated genes are expressed by microglia in the human AD brain in situ. CONCLUSIONS:Collectively, these results suggest that attenuating PU.1 may be a valid therapeutic approach to limit microglial-mediated inflammatory responses in AD and demonstrate utility of vorinostat for this purpose. en
dc.format.medium Electronic en
dc.language eng en
dc.relation.ispartofseries Molecular neurodegeneration en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.rights.uri https://creativecommons.org/licenses/by/4.0/ en
dc.subject Microglia en
dc.subject Humans en
dc.subject Alzheimer Disease en
dc.subject Trans-Activators en
dc.subject Proto-Oncogene Proteins en
dc.subject Gene Expression Regulation en
dc.subject Histone Deacetylase Inhibitors en
dc.subject Vorinostat en
dc.title PU.1 regulates Alzheimer's disease-associated genes in primary human microglia. en
dc.type Journal Article en
dc.identifier.doi 10.1186/s13024-018-0277-1 en
pubs.issue 1 en
pubs.begin-page 44 en
pubs.volume 13 en
dc.rights.holder Copyright: The authors en
pubs.publication-status Published en
dc.rights.accessrights http://purl.org/eprint/accessRights/OpenAccess en
pubs.subtype Research Support, Non-U.S. Gov't en
pubs.subtype research-article en
pubs.subtype Journal Article en
pubs.elements-id 752543 en
pubs.org-id Medical and Health Sciences en
pubs.org-id Medical Sciences en
pubs.org-id Anatomy and Medical Imaging en
pubs.org-id Pharmacology en
pubs.org-id Science en
pubs.org-id Biological Sciences en
dc.identifier.eissn 1750-1326 en
pubs.record-created-at-source-date 2018-08-21 en
pubs.dimensions-id 30124174 en


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