Multiple level interactions between

neurodegeneration and neuroinflammation in

Alzheimer s disease

Michael T. Heneka, Clinical Neuroscience, Dept. of Neurology, University of Bonn

Eibsee Meeting 2012, 21.-24.11.2012

A short tale of congo red and inflammation

Courtesy of David Brooks

PK11195-PET

AD

CON

Cytokines

Chemokines

NO, ROS, ONOO

Complement act./inhib.

TREM2

TLR2, 4, 6

TSPO

MRP14 – DAMP expression in AD

MRP14xMrp8

Cytokine/chemokine release

Recruitment of inflammatory cells

Inhibition of migration

TLR4

Kummer et al. J. Neuroscience, in press

MRP14 – regulation of microglial Aβ uptake

MRP14xMrp8TLR4

Inhibition of migroglial Aβ clearance

MRP14 – DAMP mediated BACE1/2 upregulation

BACE

MRP14xMrp8

IL-1β

TNF-α

IL-1β

TNF-α

PPARγ activation increases Aβ uptake through CD36

Yamanaka et al. J. Neuroscience, in press

PPRE

p160 CBP

coactivators

p300

PPAR RXR

PPARγ-Agonists:

NSAIDs

TZDs

Prostanoids

DHA

Increased Aβ uptake

Inflammatory gene suppression

Surveillance and trophic support

CD36

Synergistic action through dual PPARγxRXRα activation

PPRE

p160 CBP

coactivators

p300

PPAR RXR

RXR-agonists:

RA

Bexarotene

Additive / synergistic action

RXRα dependent

PPARγ activation by DSP8658 in APP/PS1 tg mice

decreased inflammation

increased phagocytosis

lowered Aβ levels

Activation of the NLRP3 inflammasome in AD

Men Mice

Heneka et al. Nature, in press

NLRP3 regulates the M1/M2 balance in microglia

M1 M2

reduced Aβ uptake

trophic factor secretion

NOS2

IL-1β

increased Aβ uptake

trophic factor secretion

ARG-1

IL-4

IDE

NLRP3 knockout prevents cognitive dysfunction

NLRP3 ko prevents Aβ induced LTP suppression

prevention of spatial memory decline

Summary

Neuroinflammation represents an important component of AD neuropathology and pathogenesis

MRP14 compromises microglial clearance

PPARgamm x RXRalpha activation resets microglial clearance function in vivo and in vitro

NLRP3 inhibition modulates microglial functions and prevents the development of cognitive impairment

Clinical Neuroscience

Dept. of Neurology

University of Bonn

Markus Kummer

Stefanie Schwarz

Ana Saeker

Delia Kurzwelly

Elisabet Reyes Irizarry

Sadanand Gaikwad

Frederic Brosseron

Francesco Santarelli

Rafael Schwarzenberger

Daisy Axt

Meltem Erylmaz

Angelika Griep

Collaborations

MPI Göttingen:

Frank Kirchhoff

Fabien Nadrigny

Umass:

Doug Golenbock

Eicke Latz

Andrea Stutz

TU Braunschweig

Anita Remus

Andrea Delekate

Martin Korte

Acknowledgements

For further information/open positions www.henekalab.com

A. Alzheimer, 1910

Former lab members

Magdalena Sastre

Marc Weberpals

Michael Hermes

Thea Hammerschmidt

Daniel Jardanhazi-Kurutz

Dick Terwel

Fadwa Tanios

Meeting announcement

For further information/open positions www.henekalab.com

Confirmed speakers

Charles Dinarello

Richard Ransohoff

Karl Herrup

Douglas Golenbock

Nicolas Bazan

Javier Vitorica

Koji Yamanaka

Gary Landreth

Greg Cole

Sally Frautschy

Clive Holmes

Hugh Perry

Erik Boddeke

Mari Shinohara

Terrence Town

Joseph El Khoury

Bertrand Brown

Guy Brown

Bente Finsen

Andreas Jacobs

David Brooks

Olga Garaschuk

Stephane Hunot

Jari Koistinaho

Monica Carson

Alex Verkrathsky