Date post: | 07-Jul-2015 |
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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
neuron tangles
plaque
microglia (innate immune cells)
Tan *, Town* et al. Science 1999 Tan*, Town* et al. Nat. Neurosci. 2002
Town et al. Nat. Med. 2008
Alzheimer’s disease pathology
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
Reduced Aβ plaques after innate immune TGF-β receptor inhibition
scale bar denotes 100 µm
CC HC EC
Tg25
76
cros
sed
perfuse mice with PBS Alzheimer pathology
Town et al., Nat. Med., 2008
Gate et al., J. Neural Transm., 2010
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
Acknowledgements University of California
Town Lab, Cedars-Sinai/UCLA Kavon Rezai-Zadeh, Ph.D. Altan Rentsendorj, 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)
David Gate
Eliezer Masliah, M.D. Charles G. Glabe, Ph.D
Yale University
Joshua J. Breunig, Ph.D.
Pasko Rakic, M.D., Ph.D.
Tara M. Weitz, Ph.D. Marie-Victoire Guillot-Sestier, Ph.D.
Novartis Pharmaceuticals Matthias Staufenbiel, Ph.D.
Tarek Fahmy, Ph.D.
Ulf Neumann, Ph.D.