Activation of innate immune response in microglia is associated with the initiation or progression of several neurodegenerative diseases. Perhaps best studied in models of Alzheimer's disease (AD), innate immune activation has been shown to have both beneficial and deleterious effects on neurons. Beneficial effects are related to the clearance of nerurotoxic species of Abeta peptides, while paracrine damage to neurons results from the elaboration of a variety of toxic substances including reactive oxygen and nitrogen species. A major goal of many academic and pharmaceutical laboratories is to identify means to augment or maintain the beneficial actions of innate immune activation while suppressing paracrine neurotoxicity. Recently we demonstrated that genetic ablation of the EP2 receptor from primary mouse microglia resulted in the highly desirable dual phenotype of an increase in phagocytosis of Abeta species and complete blockade of paracrine neurotoxicity. Others have validated our findings using different methods. Taken together, these data strongly support EP2 receptor as a highly promising target for manipulating microglial innate immune response in AD and perhaps other neurodegenerative diseases. The mechanisms by which EP2-mediated signaling is related to Abeta phagocytosis and paracrine neurotoxicity are not known. Our Preliminary Data of mouse primary microglia expression identified a candidate gene that is tightly associated to EP2. We are aware of no report on the actions of this gene in any brain cells, including microglia. However, given emerging data we hypothesize that its expression and activity are mechanistically linked to EP2 signaling and that it may be a key element by which ablation of EP2 generated the highly desirable dual phenotype of enhanced Abeta phagocytosis and reduced paracrine neurotoxicity. We will test this hypothesis through the following Specific Aims: 1) Perform in vitro validation of our candidate mRNA and protein expression in wild type and EP2-/- primary mouse microglia before and after Abeta treatment. 2) Map the in vivo regional and cellular brain distribution in wild type mice and a transgenic mouse model of AD before and after following bone-marrow transplantation from either wild type or EP2-/- mice. 3) Determine the functionality of its expression in the context of the EP2-/- dual phenotype in both knockout mice and a microglial cell line using shRNA knockdown.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F03A-F (20))
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Mackiewicz, Miroslaw
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University of Washington
Schools of Medicine
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Cimino, Patrick J; Yang, Yue; Li, Xianwu et al. (2013) Ablation of the microglial protein DOCK2 reduces amyloid burden in a mouse model of Alzheimer's disease. Exp Mol Pathol 94:366-71