title: Depletion of microglia and inhibition of exosome synthesis halt tau propagation.
abstract: Accumulation of pathological tau protein is a major hallmark of Alzheimer's disease. Tau protein spreads from the entorhinal cortex to the hippocampal region early in the disease. Microglia, the primary phagocytes in the brain, are positively correlated with tau pathology, but their involvement in tau propagation is unknown. We developed an adeno-associated virus-based model exhibiting rapid tau propagation from the entorhinal cortex to the dentate gyrus in 4 weeks. We found that depleting microglia dramatically suppressed the propagation of tau and reduced excitability in the dentate gyrus in this mouse model. Moreover, we demonstrate that microglia spread tau via exosome secretion, and inhibiting exosome synthesis significantly reduced tau propagation in vitro and in vivo. These data suggest that microglia and exosomes contribute to the progression of tauopathy and that the exosome secretion pathway may be a therapeutic target.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Hirohide
authors.initials: H
authors.lastname: Asai
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ikezu
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tsunoda
authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Medalla
authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Luebke
authors.affiliation: Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Tarik
authors.initials: T
authors.lastname: Haydar
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, USA.|Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.|Alzheimer's Disease Center, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Benjamin
authors.identifier: http://orcid.org/0000-0003-2068-1475
authors.initials: B
authors.lastname: Wolozin
authors.affiliation: Department of Neurology, Center of Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Oleg
authors.initials: O
authors.lastname: Butovsky
authors.affiliation: Center of Nanoscale Microscopy and Physiology of the Brain at Department of Neurology, University Medicine Göttingen, Göttingen, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kügler
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, USA.|Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.|Alzheimer's Disease Center, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Tsuneya
authors.initials: T
authors.lastname: Ikezu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D018728:Entorhinal Cortex / Q000473:pathology; D055354:Exosomes / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C558298:Mapt protein, mouse; D016875:tau Proteins