Webinar alzforum dec 2012 heppner
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Webinar alzforum dec 2012 heppner

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Presentation delivered by Dr. Frank Heppner, December 12, 2012 at the Alzheimer Research Forum live webinar titled "Neuroinflammation—A Prelude to Alzheimer's?" ...

Presentation delivered by Dr. Frank Heppner, December 12, 2012 at the Alzheimer Research Forum live webinar titled "Neuroinflammation—A Prelude to Alzheimer's?"

Review details at http://www.alzforum.org/res/for/journal/detail.asp?liveID=207

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Webinar alzforum dec 2012 heppner Webinar alzforum dec 2012 heppner Presentation Transcript

  • Distinct phenotypes of microglia/immune system actions in the course of AD Alzforum Webinar 12/12/12 Frank Heppner, MD Department of Neuropathology Charité – Universitätsmedizin Berlin UNIVERSITÄTSMEDIZIN BERLIN Institut für Neuropathologie
  • Distinct functions of microglia in the course of AD microglia (Iba-1) Aβ (4G8) UNIVERSITÄTSMEDIZIN BERLIN Institut für Neuropathologie
  • No change in Aβ plaque load in APPPS1-TK miceupon ablating > 95% microglia for up to 30 days Iba1/Congo Red CD11b-HSVTK X Congo Red APPPS1 Ganciclovir application for 4 weeks APPPS1-TK - APPPS1-TK+ Heppner et al., Nature Medicine 2005 Grathwohl, Kälin et al., Nature Neuroscience 2009 UNIVERSITÄTSMEDIZIN BERLIN Institut für Neuropathologie View slide
  • Why?UNIVERSITÄTSMEDIZIN BERLIN Institut für Neuropathologie View slide
  • Are microglia in AD brains really normal? UNIVERSITÄTSMEDIZIN BERLIN Institut für Neuropathologie
  • No, they aren’t:•Impaired microglial response to acute tissue lesions in plaque-carryingAPPPS1 mice – 2P realtime imaging• Impaired microglial phagocytosis of latex beads in APPPS1 mice in the presence of AβAnd, notably:•rescue of microglial phagocytosis activity upon Aβ vaccination-based Aβreduction Krabbe, Halle et al., submitted UNIVERSITÄTSMEDIZIN BERLIN Institut für Neuropathologie
  • Further phenotyping microglia in AD:Upregulation of microglial IL-12/23p40 in APPPS1 mice Vom Berg, Prokop et al., Nature Medicine 2012 UNIVERSITÄTSMEDIZIN BERLIN Institut für Neuropathologie
  • Drastic reduction of Aβ plaque load in APPPS1mice lacking IL-12 and / or IL-23 Vom Berg, Prokop et al., Nature Medicine 2012 UNIVERSITÄTSMEDIZIN BERLIN Institut für Neuropathologie
  • Drastic reduction of Aβ plaque load in APPPS1mice lacking IL-12 and / or IL-23 Vom Berg, Prokop et al., Nature Medicine 2012 UNIVERSITÄTSMEDIZIN BERLIN Institut für Neuropathologie
  • ConclusionsPhenotypes of microglia in AD1. Dysfunction (i.e. lack of function) of microglia in APPPS1 mice over time, possiblydue to chronic Aβ exposure and/or to chronic inflammatory microenvironment  Temporary ablation of microglia (up to 30 days) „doesn‘t matter“ (longer periods have not been tried due to technical limitations of the model)  Does AD pathology exacerbate due to the lack of microglia function?  However: microglia phenotype is reversible (e.g. by means of Aβ vaccination)!2. (over)production of cytokines, including IL-12 and IL-23, which exacerbateAD-like pathology  Blocking of IL-12/23 (genetically, or pharmacologically for at least 60 days) results in alleviation of AD-like pathology (plaque burden, behaviour) UNIVERSITÄTSMEDIZIN BERLIN Institut für Neuropathologie
  • Conclusions • It very much depends, when certain (microglial) immune molecules act, and for how long they act • In turn, it matters, which specific immune components will be manipulated, when and for how long • Thus, we need to dissect the impact of distinct immune components in more detail. There is no such thing as exclusively „good“ or „bad“ microglia /„the immune reaction“ in AD UNIVERSITÄTSMEDIZIN BERLIN Institut für Neuropathologie
  • Heppner lab: Burkhard Becher Johannes vom Berg Ulrike Bernhardt Institut für Johannes von Büren Experimentelle Immunologie Natalia Drost Universitätsspital Zürich Gina Eom Claire Gehlhaar Susann Handrick Mathias Jucker Nicole Henschel Stefan Grathwohl Roland Kälin Department of Cellular Neurology Kerstin Kopp Hertie-Institute of Stefanie Kraft Clinical Brain Research Petra Matylewski University of Tübingen Kelly Miller Ray Monk Helmut Kettenmann Juliane Obst Grietje Krabbe Department of Neuropathology Debora Pehl Charité – Universitätsmedizin Berlin Max Delbrück Center Stefan Prokop for Molecular Medicine Bianca Richter Berlin funded by Jan Leo Rinnenthal NIH (NINDS R01 NS046006) Carola Schipke Lisa Wagner Annett Halle NeuroCure excellence cluster (DFG) Anja Wegner Caesar EU FP7 HEALTH (Project LUPAS) Gordon Wilke BonnKompetenznetzes Degenerative Demenzen (BMBF) SFB TRR 43 (DFG) UNIVERSITÄTSMEDIZIN BERLIN Institut für Neuropathologie