title: CD45RB is a novel molecular therapeutic target to inhibit Abeta peptide-induced microglial MAPK activation.
abstract: BACKGROUND
  Microglial activation, characterized by p38 MAPK or p44/42 MAPK pathway signal transduction, occurs in Alzheimer's disease (AD). Our previous studies demonstrated CD45, a membrane-bound protein tyrosine phosphatase (PTP), opposed beta-amyloid (Abeta) peptide-induced microglial activation via inhibition of p44/42 MAPK. Additionally we have shown agonism of the RB isoform of CD45 (CD45RB) abrogates lipopolysaccharide (LPS)-induced microglial activation.
  
  
  RESULTS
  In this study, CD45RB modulation of Abeta peptide or LPS-activated primary cultured microglial cells was further investigated. Microglial cells were co-treated with "aged" FITC-Abeta(1-42) and multiple CD45 isoform agonist antibodies. Data revealed cross-linking of CD45, particularly the CD45RB isoform, enhances microglial phagocytosis of Abeta(1-42) peptide and inhibits LPS-induced activation of p44/42 and p38 pathways. Co-treatment of microglial cells with agonist CD45 antibodies results in significant inhibition of LPS-induced microglial TNF-alpha and IL-6 release through p44/42 and/or p38 pathways. Moreover, inhibition of either of these pathways augmented CD45RB cross-linking induced microglial phagocytosis of Abeta(1-42) peptide. To investigate the mechanism(s) involved, microglial cells were co-treated with a PTP inhibitor (potassium bisperoxo [1,10-phenanthroline oxovanadate; Phen]) and Abeta(1-42) peptides. Data showed synergistic induction of microglial activation as evidenced by TNF-alpha and IL-6 release; both of which are demonstrated to be dependent on increased p44/42 and/or p38 activation. Finally, it was observed that cross-linking of CD45RB in the presence of Abeta(1-42) peptide, inhibits co-localization of microglial MHC class II and Abeta peptide; suggesting CD45 activation inhibits the antigen presenting phenotype of microglial cells.
  
  
  CONCLUSIONS
  In summary, p38 MAPK is another novel signaling pathway, besides p44/42, in which CD45RB cross-linking negatively regulates microglial Abeta phagocytosis while increasing potentially neurotoxic inflammation. Therefore, agonism of CD45RB PTP activity may be an effective therapeutic target for novel agents to treat AD due to its Abeta lowering, and inflammation reducing, properties that are particularly targeted at microglial cells. Such treatments may be more effective with less potential to produce systemic side-effects than therapeutics which induce non-specific, systemic down-regulation of inflammation.
authors.affiliation: Rashid Laboratory Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida, United States of America.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Huayan
authors.initials: H
authors.lastname: Hou
authors.forename: William V
authors.initials: WV
authors.lastname: Nikolic
authors.forename: Jared
authors.initials: J
authors.lastname: Ehrhart
authors.forename: Elona
authors.initials: E
authors.lastname: Rrapo
authors.forename: Paula
authors.initials: P
authors.lastname: Bickford
authors.forename: Brian
authors.initials: B
authors.lastname: Giunta
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D003470:Culture Media; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D015850:Interleukin-6 / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000201:enzymology*; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010587:Phagocytosis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D003470:Culture Media; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D017493:Leukocyte Common Antigens