Terrence Town - Neuroinflammation

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

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Terrence Town - Neuroinflammation

  1. 1. Targeting ‘good’ neuroinflammation in Alzheimer’s disease Terrence Town, Ph.D. Ben Winters Professor of Regenerative Medicine Regenerative Medicine Institute at Cedars-Sinai Medical Center/UCLA *NOTHING TO DISCLOSE
  2. 2. Alzheimer’s disease pathology plaquetangles neuron Tan *, Town* et al. Science 1999 Tan*, Town* et al. Nat. Neurosci. 2002 Town et al. Nat. Med. 2008 microglia (innate immune cells)
  3. 3. Neuroinflammation in AD: the good, the bad, and the ugly• Retrospective epidemiology: inverse risk relationship between NSAIDs and AD• Primary prevention clinical trial (ADAPT): are NSAIDs protective?• Beneficial microgliosis – the Elan/Wyeth AN-1792 Aβ1-42 vaccine trial• Contemporary view: different forms of neuro- inflammation- some helpful, others deleterious
  4. 4. Reduced Aβ plaques after innate immune TGF-β receptor inhibition perfuse mice with PBS Alzheimer pathology CC HC EC Tg2576 crossedTown et al., Nat. Med., 2008 scale bar denotes 100 µm
  5. 5. Gate et al., J. Neural Transm., 2010
  6. 6. Conclusions• Blockade of macrophage anti-inflammatory TGF-β signaling activates plaque clearance• Deletion of a related key anti-inflammatory molecule, IL-10, targets microglial Aβ clearance• Promoting inflammation in IRAK-M knockouts endorses microglial activation to clear Aβ• These ‘good’ forms of neuroinflammation do not appear to come at the cost of bystander neurotoxicity
  7. 7. Acknowledgements University of California Eliezer Masliah, M.D. Charles G. Glabe, Ph.D Yale University Tarek Fahmy, Ph.D. Pasko Rakic, M.D., Ph.D. Novartis Pharmaceuticals Matthias Staufenbiel, Ph.D. Town Lab, Cedars-Sinai/UCLA Ulf Neumann, Ph.D. Kavon Rezai-Zadeh, Ph.D. Altan Rentsendorj, Ph.D. David Gate Joshua J. Breunig, Ph.D. Tara M. Weitz, Ph.D. Marie-Victoire Guillot-Sestier, Ph.D.Alzheimer’s Association (IIRG-0514993, ZEN-10-174633), Ellison Medical Foundation/AFAR Julie Martin Mid-Career Award (M11472), NIH/NIA (AG029726), and NIH/NINDS (R01 NS076794)
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