Presentation made December 12, 2012 at the live webinar hosted by the Alzheimer Research Forum - http://www.alzforum.org/res/for/journal/detail.asp?liveID=207

1. 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

2. A short tale of congo red and inflammation
PK11195-PET
Cytokines
Chemokines CON
NO, ROS, ONOO
AD
Complement act./inhib.
TREM2
TLR2, 4, 6
TSPO
Courtesy of David Brooks

3. MRP14 – DAMP expression in AD
TLR4 MRP14xMrp8
Cytokine/chemokine release
Recruitment of inflammatory cells
Inhibition of migration
Kummer et al. J. Neuroscience, in press

4. MRP14 – regulation of microglial Aβ uptake
TLR4 MRP14xMrp8
Inhibition of migroglial Aβ clearance

5. MRP14 – DAMP mediated BACE1/2 upregulation
IL-1β MRP14xMrp8
TNF-α
BACE
IL-1β
TNF-α

6. PPARγ activation increases Aβ uptake through CD36
PPARγ-Agonists:
NSAIDs
TZDs
Prostanoids
DHA
coactivators
p300 p160 CBP
PPAR RXR
PPRE
CD36
Increased Aβ uptake
Inflammatory gene suppression
Surveillance and trophic support Yamanaka et al. J. Neuroscience, in press

7. Synergistic action through dual PPARγxRXRα activation
RXR-agonists:
RA
Bexarotene
coactivators
p300 p160 CBP
PPAR RXR
PPRE
Additive / synergistic action
RXRα dependent

8. PPARγ activation by DSP8658 in APP/PS1 tg mice
decreased inflammation
increased phagocytosis
lowered Aβ levels

9. Activation of the NLRP3 inflammasome in AD
Men Mice
Heneka et al. Nature, in press

10. NLRP3 regulates the M1/M2 balance in microglia
M1 M2
reduced Aβ uptake increased Aβ uptake
trophic factor secretion trophic factor secretion
NOS2 ARG-1
IL-1β IL-4
IDE

11. NLRP3 knockout prevents cognitive dysfunction
NLRP3 ko prevents Aβ induced LTP suppression
prevention of spatial memory decline

12. 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

13. Acknowledgements
Clinical Neuroscience Collaborations
Dept. of Neurology
University of Bonn MPI Göttingen:
Markus Kummer Frank Kirchhoff
Stefanie Schwarz Fabien Nadrigny
Ana Saeker
Delia Kurzwelly Umass:
Elisabet Reyes Irizarry Doug Golenbock
Sadanand Gaikwad Eicke Latz
Frederic Brosseron Andrea Stutz
Francesco Santarelli
Rafael Schwarzenberger TU Braunschweig
Daisy Axt Anita Remus
Meltem Erylmaz Andrea Delekate
Angelika Griep Martin Korte
Former lab members
Magdalena Sastre
Marc Weberpals
Michael Hermes A. Alzheimer, 1910
Thea Hammerschmidt
Daniel Jardanhazi-Kurutz
Dick Terwel
Fadwa Tanios
For further information/open positions www.henekalab.com

14. Meeting announcement
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
For further information/open positions www.henekalab.com