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.