title: Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway.
abstract: Several Alzheimer's disease (AD) risk genes are specifically expressed by microglia within the CNS. However, the mechanisms by which microglia regulate the pathological hallmarks of AD--extracellular deposition of β-amyloid (Aβ) and intraneuronal hyperphosphorylation of microtubule-associated protein tau (MAPT)--remain to be established. Notably, deficiency for the microglial CX3CR1 receptor has opposing effects on Aβ and MAPT pathologies. CX3CL1, the neuronally derived cognate ligand for CX3CR1, signals both in membrane-anchored and soluble forms. In this study, we sought to determine the relative contribution on membrane-anchored versus soluble CX3CL1 in regulating the microglia-mediated amelioration of Aβ pathology, as well as provide insight into the potential downstream microglial-based mechanisms. As expected, CX3CL1 deficiency reduced Aβ deposition in APPPS1 animals in a similar manner to CX3CR1 deficiency. Surprisingly, however, CX3CL1-deficient APPPS1 animals exhibited enhanced neuronal MAPT phosphorylation despite reduced amyloid burden. Importantly, neither of these phenotypes was altered by transgenic expression of the soluble CX3CL1 isoform, suggesting that it is the membrane-anchored version of CX3CL1 that regulates microglial phagocytosis of Aβ and neuronal MAPT phosphorylation. Analysis of transcript levels in purified microglia isolated from APPPS1 mice with the various CX3CL1/CX3CR1 genotypes revealed increased expression of inflammatory cytokines and phagocytic markers, which was associated with activation of p38 mitogen-activated protein kinase and Aβ internalization within microglia. Together, these studies challenge the "frustrated phagocytosis" concept and suggest that neuronal-microglial communication link the two central AD pathologies.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and.
authors.forename: Sungho
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Guixiang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and.
authors.forename: Taylor R
authors.initials: TR
authors.lastname: Jay
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Sabina
authors.initials: S
authors.lastname: Bhatta
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Ki-Wook
authors.identifier: http://orcid.org/0000-0002-7207-4389
authors.initials: KW
authors.lastname: Kim
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Landreth
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, Department of Genetics and Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, and lambb@ccf.org.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lamb
mesh_terms: D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000378:metabolism*; D005260:Female; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D016875:tau Proteins; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Alzheimer's disease; CX3CL1; microglia; phagocytosis