DOCK2 is a microglial specific regulator of central nervous system innate immunity found in normal and Alzheimer's disease brain.
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 Abeta 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.
Cimino
Patrick J
PJ
Division of Neuropathology, Department of Pathology, the Neurobiology and Behavior Program, University of Washington, Box 359645, Harborview Medical Center, Seattle, WA 98104, USA. pjjc@u.washington.edu
Sokal
Izabela
I
Leverenz
James
J
Fukui
Yoshinori
Y
Montine
Thomas J
TJ
D000544:Alzheimer Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype
C402110:DOCK2 protein, human; C471356:DOCK2 protein, mouse; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; C545644:PTGER2 protein, human; C545645:Ptger2 protein, mouse; D012333:RNA, Messenger; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2