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Originally published online as doi:10.2353/ajpath.2009.090443 on September 3, 2009

Published online before print September 3, 2009
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(American Journal of Pathology. 2009;175:1622-1630.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.090443

DOCK2 Is a Microglial Specific Regulator of Central Nervous System Innate Immunity Found in Normal and Alzheimer’s Disease Brain

Patrick J. Cimino*{dagger}, Izabela Sokal*, James Leverenz{ddagger}, Yoshinori Fukui§ and Thomas J. Montine*{dagger}

From the Department of Pathology,* the Neurobiology and Behavior Program,{dagger} and the Department of Neurology,{ddagger} University of Washington School of Medicine, Seattle, Washington; the Division of Immunogenetics,§ Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; and the Japan Science and Technology Agency, CREST, Tokyo, Japan

Neuroinflammation is a hallmark of several neurodegenerative diseases, including Alzheimer’s disease (AD). Strong epidemiological and experimental evidence supports the use of nonsteroidal anti-inflammatory drugs to reduce AD risk. However, poor outcome in clinical trials and toxicity in a prevention trial have shifted focus away from these cyclooxygenase (COX) inhibitors to seek additional therapeutic targets in the prostaglandin pathway. Previously, the prostaglandin E2 receptor, EP2, was shown to regulate neuroinflammation and reduce Aβ plaque burden in transgenic mice. Unfortunately, widespread EP2 distribution and a direct effect on COX2 induction make EP2 a less desirable target. In this study, we link dedicator of cytokinesis 2 (DOCK2) to the prostaglandin pathway in the brain. Additionally, we show that DOCK2 regulates microglial innate immunity independent of COX2 induction and that DOCK2+ microglia are associated with human AD pathology. Together, these results suggest DOCK2 as a COX2 expression-independent therapeutic target for neurodegenerative diseases such as AD.






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Copyright © 2009 by the American Society for Investigative Pathology.