title: Accelerated neurodegeneration and neuroinflammation in transgenic mice expressing P301L tau mutant and tau-tubulin kinase 1.
abstract: Tau-tubulin kinase-1 (TTBK1) is a central nervous system (CNS)-specific protein kinase implicated in the pathological phosphorylation of tau. TTBK1-transgenic mice show enhanced neuroinflammation in the CNS. Double-transgenic mice expressing TTBK1 and frontotemporal dementia with parkinsonism-17-linked P301L (JNPL3) tau mutant (TTBK1/JNPL3) show increased accumulation of oligomeric tau protein in the CNS and enhanced loss of motor neurons in the ventral horn of the lumbar spinal cord. To determine the role of TTBK1-induced neuroinflammation in tauopathy-related neuropathogenesis, age-matched TTBK1/JNPL3, JNPL3, TTBK1, and non-transgenic littermates were systematically characterized. There was a striking switch in the activation phenotype and population of mononuclear phagocytes (resident microglia and infiltrating macrophages) in the affected spinal cord region: JNPL3 mice showed accumulation of alternatively activated microglia, whereas TTBK1 and TTBK1/JNPL3 mice showed accumulation of classically activated infiltrating peripheral monocytes. In addition, expression of chemokine ligand 2, a chemokine important for the recruitment of peripheral monocytes, was enhanced in TTBK1 and TTBK1/JNPL3 but not in other groups in the spinal cord. Furthermore, primary cultured mouse motor neurons showed axonal degeneration after transient expression of the TTBK1 gene or treatment with conditioned media derived from lipopolysaccharide-stimulated microglia; this was partially blocked by silencing of the endogenous TTBK1 gene in neurons. These data suggest that TTBK1 accelerates motor neuron neurodegeneration by recruiting proinflammatory monocytes and enhancing sensitivity to neurotoxicity in inflammatory conditions.
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Hirohide
authors.initials: H
authors.lastname: Asai
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ikezu
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Maya E
authors.initials: ME
authors.lastname: Woodbury
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Grant M S
authors.initials: GM
authors.lastname: Yonemoto
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Libin
authors.initials: L
authors.lastname: Cui
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts; Department of Neurology, Boston University School of Medicine, Boston, Massachusetts; Alzheimer's Disease Center, Boston University School of Medicine, Boston, Massachusetts. Electronic address: tikezu@bu.edu.
authors.forename: Tsuneya
authors.initials: T
authors.lastname: Ikezu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D016875:tau Proteins; C095903:tau-tubulin kinase; D017346:Protein Serine-Threonine Kinases