DOCK2 is a microglial specific regulator of central nervous system innate immunity found in normal and Alzheimer's disease brain

Patrick J. Cimino, Izabela Sokal, James Leverenz, Yoshinori Fukui, Thomas J. Montine

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1622-1630
Number of pages9
JournalAmerican Journal of Pathology
Volume175
Issue number4
DOIs
Publication statusPublished - Jan 1 2009

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Cytokinesis
Innate Immunity
Alzheimer Disease
Central Nervous System
Brain
Neurodegenerative Diseases
Prostaglandins
Prostaglandin Receptors
Cyclooxygenase Inhibitors
Microglia
Dinoprostone
Transgenic Mice
Anti-Inflammatory Agents
Clinical Trials
Pathology
Therapeutics
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

DOCK2 is a microglial specific regulator of central nervous system innate immunity found in normal and Alzheimer's disease brain. / Cimino, Patrick J.; Sokal, Izabela; Leverenz, James; Fukui, Yoshinori; Montine, Thomas J.

In: American Journal of Pathology, Vol. 175, No. 4, 01.01.2009, p. 1622-1630.

Research output: Contribution to journalArticle

Cimino, Patrick J. ; Sokal, Izabela ; Leverenz, James ; Fukui, Yoshinori ; Montine, Thomas J. / DOCK2 is a microglial specific regulator of central nervous system innate immunity found in normal and Alzheimer's disease brain. In: American Journal of Pathology. 2009 ; Vol. 175, No. 4. pp. 1622-1630.
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