Heneka

10,156 views
10,188 views

Published on

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

Published in: Health & Medicine
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
10,156
On SlideShare
0
From Embeds
0
Number of Embeds
6,058
Actions
Shares
0
Downloads
13
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

Heneka

  1. 1. Multiple level interactions betweenneurodegeneration and neuroinflammation inAlzheimer s diseaseMichael T. Heneka, Clinical Neuroscience, Dept. of Neurology, University of BonnEibsee Meeting 2012, 21.-24.11.2012
  2. 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. 3. MRP14 – DAMP expression in AD TLR4 MRP14xMrp8Cytokine/chemokine releaseRecruitment of inflammatory cellsInhibition of migration Kummer et al. J. Neuroscience, in press
  4. 4. MRP14 – regulation of microglial Aβ uptake TLR4 MRP14xMrp8Inhibition of migroglial Aβ clearance
  5. 5. MRP14 – DAMP mediated BACE1/2 upregulationIL-1β MRP14xMrp8TNF-αBACE IL-1β TNF-α
  6. 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. 7. Synergistic action through dual PPARγxRXRα activation RXR-agonists: RA Bexarotene coactivators p300 p160 CBP PPAR RXR PPRE Additive / synergistic action RXRα dependent
  8. 8. PPARγ activation by DSP8658 in APP/PS1 tg mice decreased inflammation increased phagocytosis lowered Aβ levels
  9. 9. Activation of the NLRP3 inflammasome in AD Men Mice Heneka et al. Nature, in press
  10. 10. NLRP3 regulates the M1/M2 balance in microglia M1 M2 reduced Aβ uptake increased Aβ uptaketrophic factor secretion trophic factor secretion NOS2 ARG-1 IL-1β IL-4 IDE
  11. 11. NLRP3 knockout prevents cognitive dysfunction NLRP3 ko prevents Aβ induced LTP suppression prevention of spatial memory decline
  12. 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. 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. 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

×