TY - JOUR
T1 - Accelerated neurodegeneration and neuroinflammation in transgenic mice expressing P301L tau mutant and tau-tubulin kinase 1
AU - Asai, Hirohide
AU - Ikezu, Seiko
AU - Woodbury, Maya E.
AU - Yonemoto, Grant M.S.
AU - Cui, Libin
AU - Ikezu, Tsuneya
N1 - Funding Information:
This work is supported in part by BrightFocus Foundation for Alzheimer Disease Research (H.A.), NIH grant 5T32GM008541 (M.W.), Boston University Undergraduate Research Opportunities Program Award (G.M.S.Y.), Alzheimer's Art Quilt Initiative (T.I.), and Boston University Faculty Recruit Fund (T.I.).
PY - 2014/3
Y1 - 2014/3
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2013.11.026
DO - 10.1016/j.ajpath.2013.11.026
M3 - Article
C2 - 24418258
AN - SCOPUS:84894189382
SN - 0002-9440
VL - 184
SP - 808
EP - 818
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 3
ER -