U N I V E R S I T Ä T S M E D I Z I N B E R L I N Institut für Neuropathologie

Distinct phenotypes of microglia/immune system actions

in the course of AD

Alzforum Webinar 12/12/12

Frank Heppner, MDDepartment of Neuropathology

Charité – Universitätsmedizin Berlin

U N I V E R S I T Ä T S M E D I Z I N B E R L I N Institut für Neuropathologie

Distinct functions of microglia in the course of AD

microglia (Iba-1)Aβ (4G8)

U N I V E R S I T Ä T S M E D I Z I N B E R L I N Institut für Neuropathologie

APPPS1

APPPS1-TK+APPPS1-TK -

CD11b-HSVTK

X

Ganciclovir application for 4 weeks

No change in Aβ plaque load in APPPS1-TK mice upon ablating > 95% microglia for up to 30 days

Co

ng

o R

edIb

a1/C

on

go

Red

Heppner et al., Nature Medicine 2005Grathwohl, Kälin et al., Nature Neuroscience 2009

U N I V E R S I T Ä T S M E D I Z I N B E R L I N Institut für Neuropathologie

Why?

U N I V E R S I T Ä T S M E D I Z I N B E R L I N Institut für Neuropathologie

Are microglia in AD brains really normal?

U N I V E R S I T Ä T S M E D I Z I N B E R L I N Institut für Neuropathologie

Krabbe, Halle et al., submitted

No, they aren’t:

•Impaired microglial response to acute tissue lesions in plaque-carrying APPPS1 mice – 2P realtime imaging

• Impaired microglial phagocytosis of latex beads in APPPS1 mice in the presence of Aβ

And, notably:

•rescue of microglial phagocytosis activity upon Aβ vaccination-based Aβ reduction

U N I V E R S I T Ä T S M E D I Z I N B E R L I N 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

U N I V E R S I T Ä T S M E D I Z I N B E R L I N Institut für Neuropathologie

Drastic reduction of Aβ plaque load in APPPS1 mice lacking IL-12 and / or IL-23

Vom Berg, Prokop et al., Nature Medicine 2012

U N I V E R S I T Ä T S M E D I Z I N B E R L I N Institut für Neuropathologie

Drastic reduction of Aβ plaque load in APPPS1 mice lacking IL-12 and / or IL-23

Vom Berg, Prokop et al., Nature Medicine 2012

U N I V E R S I T Ä T S M E D I Z I N B E R L I N Institut für Neuropathologie

Conclusions

Phenotypes of microglia in AD

1. Dysfunction (i.e. lack of function) of microglia in APPPS1 mice over time, possibly due 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 exacerbate

AD-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)

U N I V E R S I T Ä T S M E D I Z I N B E R L I N 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

U N I V E R S I T Ä T S M E D I Z I N B E R L I N Institut für Neuropathologie

Department of Cellular NeurologyHertie-Institute of

Clinical Brain ResearchUniversity of Tübingen

Mathias JuckerStefan Grathwohl

Institut für Experimentelle Immunologie

Universitätsspital Zürich

Burkhard BecherJohannes vom Berg

funded byNIH (NINDS R01 NS046006)

NeuroCure excellence cluster (DFG)EU FP7 HEALTH (Project LUPAS)

Kompetenznetzes Degenerative Demenzen (BMBF)SFB TRR 43 (DFG)

Helmut KettenmannGrietje Krabbe

Max Delbrück Center for Molecular Medicine

Berlin

Department of NeuropathologyCharité – Universitätsmedizin Berlin

Annett HalleCaesarBonn

Heppner lab:

Ulrike BernhardtJohannes von Büren

Natalia DrostGina Eom

Claire GehlhaarSusann HandrickNicole Henschel

Roland Kälin Kerstin KoppStefanie Kraft

Petra MatylewskiKelly MillerRay Monk

Juliane ObstDebora Pehl

Stefan ProkopBianca Richter

Jan Leo RinnenthalCarola Schipke

Lisa WagnerAnja Wegner

Gordon Wilke