Opposing Effects of Membrane-Anchored CX3CL1 on Amyloid and Tau Pathologies via the p38 MAPK Pathway

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.

[1]  R. Tanzi,et al.  ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function , 2013, Neuron.

[2]  P. Bickford,et al.  Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy , 2013, Neurobiology of Aging.

[3]  F. LaFerla,et al.  Sustained Interleukin-1β Overexpression Exacerbates Tau Pathology Despite Reduced Amyloid Burden in an Alzheimer's Mouse Model , 2013, The Journal of Neuroscience.

[4]  Jean-Philippe Michaud,et al.  Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology , 2013, Proceedings of the National Academy of Sciences.

[5]  A. Singleton,et al.  TREM2 variants in Alzheimer's disease. , 2013, The New England journal of medicine.

[6]  A. Hofman,et al.  Variant of TREM2 associated with the risk of Alzheimer's disease. , 2013, The New England journal of medicine.

[7]  York Winter,et al.  Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease–like pathology and cognitive decline , 2012, Nature Medicine.

[8]  P. Bickford,et al.  The Soluble Isoform of CX3CL1 Is Necessary for Neuroprotection in a Mouse Model of Parkinson's Disease , 2012, The Journal of Neuroscience.

[9]  T. Golde,et al.  Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition , 2012, Molecular Neurodegeneration.

[10]  D. Borchelt,et al.  Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function , 2012, Neurobiology of Aging.

[11]  Steffen Jung,et al.  In vivo structure/function and expression analysis of the CX3C chemokine fractalkine. , 2011, Blood.

[12]  F. Jessen,et al.  Nitration of Tyrosine 10 Critically Enhances Amyloid β Aggregation and Plaque Formation , 2011, Neuron.

[13]  P. Popovich,et al.  Deficient CX3CR1 Signaling Promotes Recovery after Mouse Spinal Cord Injury by Limiting the Recruitment and Activation of Ly6Clo/iNOS+ Macrophages , 2011, The Journal of Neuroscience.

[14]  Nick C Fox,et al.  Common variants in ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease , 2011, Nature Genetics.

[15]  D. G. Clark,et al.  Common variants in MS4A4/MS4A6E, CD2uAP, CD33, and EPHA1 are associated with late-onset Alzheimer’s disease , 2011, Nature Genetics.

[16]  T. Golde,et al.  Hippocampal expression of murine TNFα results in attenuation of amyloid deposition in vivo , 2011, Molecular Neurodegeneration.

[17]  J. Grutzendler,et al.  CX3CR1 in Microglia Regulates Brain Amyloid Deposition through Selective Protofibrillar Amyloid-β Phagocytosis , 2010, The Journal of Neuroscience.

[18]  R. Ransohoff,et al.  CX3CR1 deficiency alters microglial activation and reduces beta-amyloid deposition in two Alzheimer's disease mouse models. , 2010, The American journal of pathology.

[19]  R. Ransohoff,et al.  Regulation of Tau Pathology by the Microglial Fractalkine Receptor , 2010, Neuron.

[20]  D. Dickson,et al.  IFN-γ Promotes Complement Expression and Attenuates Amyloid Plaque Deposition in Amyloid β Precursor Protein Transgenic Mice , 2010, The Journal of Immunology.

[21]  D. Dickson,et al.  Massive gliosis induced by interleukin‐6 suppresses Aβ deposition in vivo: evidence against inflammation as a driving force for amyloid deposition , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[22]  B. Turk,et al.  Active-site determinants of substrate recognition by the metalloproteinases TACE and ADAM10. , 2009, The Biochemical journal.

[23]  L. Kiemeney,et al.  Corrigendum: Genetic variation in the prostate stem cell antigen gene PSCA confers susceptibility to urinary bladder cancer , 2009, Nature Genetics.

[24]  G. Landreth,et al.  CD14 and Toll-Like Receptors 2 and 4 Are Required for Fibrillar Aβ-Stimulated Microglial Activation , 2009, The Journal of Neuroscience.

[25]  Nick C Fox,et al.  Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease, and shows evidence for additional susceptibility genes , 2009, Nature Genetics.

[26]  P. Bosco,et al.  Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease , 2009, Nature Genetics.

[27]  H. Braak,et al.  Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease , 2009, Acta Neuropathologica.

[28]  D. Holtzman,et al.  Rapid Microglial Response Around Amyloid Pathology after Systemic Anti-Aβ Antibody Administration in PDAPP Mice , 2008, The Journal of Neuroscience.

[29]  Z. Környei,et al.  Role of CX3CR1 (Fractalkine Receptor) in Brain Damage and Inflammation Induced by Focal Cerebral Ischemia in Mouse , 2008, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[30]  C. Lemere,et al.  Complement C3 Deficiency Leads to Accelerated Amyloid β Plaque Deposition and Neurodegeneration and Modulation of the Microglia/Macrophage Phenotype in Amyloid Precursor Protein Transgenic Mice , 2008, The Journal of Neuroscience.

[31]  Hartwig Wolburg,et al.  Aβ42‐driven cerebral amyloidosis in transgenic mice reveals early and robust pathology , 2006, EMBO reports.

[32]  Steffen Jung,et al.  Control of microglial neurotoxicity by the fractalkine receptor , 2006, Nature Neuroscience.

[33]  C. Blobel,et al.  Adam Meets Eph: An ADAM Substrate Recognition Module Acts as a Molecular Switch for Ephrin Cleavage In trans , 2005, Cell.

[34]  James L. Buescher,et al.  Overexpression of monocyte chemotactic protein-1/ CCL2 in β-amyloid precursor protein transgenic mice show accelerated diffuse β-amyloid deposition , 2005 .

[35]  F. Fahrenholz,et al.  The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. , 2003, Blood.

[36]  S. Barger,et al.  Interleukin-1 Mediates Pathological Effects of Microglia on Tau Phosphorylation and on Synaptophysin Synthesis in Cortical Neurons through a p38-MAPK Pathway , 2003, The Journal of Neuroscience.

[37]  C. Blobel,et al.  Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1). , 2001, The Journal of biological chemistry.

[38]  K. Ashe,et al.  Ibuprofen Suppresses Plaque Pathology and Inflammation in a Mouse Model for Alzheimer's Disease , 2000, The Journal of Neuroscience.

[39]  Wei Wang,et al.  A new class of membrane-bound chemokine with a CX3C motif , 1997, Nature.

[40]  F. Maxfield,et al.  Microglial Cells Internalize Aggregates of the Alzheimer's Disease Amyloid β-Protein Via a Scavenger Receptor , 1996, Neuron.

[41]  D. G. Clark,et al.  Common variants at MS 4 A 4 / MS 4 A 6 E , CD 2 AP , CD 33 and EPHA 1 are associated with late-onset Alzheimer ’ s disease , 2011 .

[42]  Nick C Fox,et al.  Common variants at ABCA 7 , MS 4 A 6 A / MS 4 A 4 E , EPHA 1 , CD 33 and CD 2 AP are associated with Alzheimer ’ s disease , 2011 .

[43]  James L. Buescher,et al.  Overexpression of monocyte chemotactic protein-1/CCL2 in beta-amyloid precursor protein transgenic mice show accelerated diffuse beta-amyloid deposition. , 2005, The American journal of pathology.

[44]  L. Mucke,et al.  TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. , 2001, Nature medicine.