title: Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain.
abstract: Pathological aggregation of tau is a hallmark of Alzheimer's disease and related tauopathies. We have previously shown that the deficiency of the microglial fractalkine receptor (CX3CR1) led to the acceleration of tau pathology and memory impairment in an hTau mouse model of tauopathy. Here, we show that microglia drive tau pathology in a cell-autonomous manner. First, tau hyperphosphorylation and aggregation occur as early as 2 months of age in hTauCx3cr1(-/-) mice. Second, CD45(+) microglial activation correlates with the spatial memory deficit and spread of tau pathology in the anatomically connected regions of the hippocampus. Third, adoptive transfer of purified microglia derived from hTauCx3cr1(-/-) mice induces tau hyperphosphorylation within the brains of non-transgenic recipient mice. Finally, inclusion of interleukin 1 receptor antagonist (Kineret®) in the adoptive transfer inoculum significantly reduces microglia-induced tau pathology. Together, our results suggest that reactive microglia are sufficient to drive tau pathology and correlate with the spread of pathological tau in the brain.
authors.affiliation: 1 Department of Molecular Genetics and Microbiology, MSC08 4660, 1 University of New Mexico, University of New Mexico, Albuquerque NM 87131, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Maphis
authors.affiliation: 2 Department of Neurosciences, NC30, 9500 Euclid Avenue, Cleveland Clinic, Cleveland OH 44195, USA.
authors.forename: Guixiang
authors.initials: G
authors.lastname: Xu
authors.affiliation: 2 Department of Neurosciences, NC30, 9500 Euclid Avenue, Cleveland Clinic, Cleveland OH 44195, USA.
authors.forename: Olga N
authors.initials: ON
authors.lastname: Kokiko-Cochran
authors.affiliation: 1 Department of Molecular Genetics and Microbiology, MSC08 4660, 1 University of New Mexico, University of New Mexico, Albuquerque NM 87131, USA.
authors.forename: Shanya
authors.initials: S
authors.lastname: Jiang
authors.affiliation: 3 Department of Biology, University of Texas San Antonio, West Campus/Tobin lab MBT 1.216, San Antonio TX 78249, USA.
authors.forename: Astrid
authors.initials: A
authors.lastname: Cardona
authors.affiliation: 4 Biogen Idec, 225 Binney Street, Cambridge, MA 02142, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.affiliation: 2 Department of Neurosciences, NC30, 9500 Euclid Avenue, Cleveland Clinic, Cleveland OH 44195, USA.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lamb
authors.affiliation: 1 Department of Molecular Genetics and Microbiology, MSC08 4660, 1 University of New Mexico, University of New Mexico, Albuquerque NM 87131, USA KBhaskar@salud.unm.edu KBhaskar@unm.edu.
authors.forename: Kiran
authors.initials: K
authors.lastname: Bhaskar
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D000073883:CX3C Chemokine Receptor 1; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D008569:Memory Disorders / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D061251:Primary Cell Culture; D066329:Protein Aggregates / Q000235:genetics; D019707:Receptors, Chemokine / Q000172:deficiency / Q000235:genetics; D024801:Tauopathies / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D066329:Protein Aggregates; D019707:Receptors, Chemokine; D016875:tau Proteins
keywords: Alzheimer’s disease; microglia; neuroinflammation; tau protein; tauopathies
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