title: Hyperactive glial cells contribute to axonal pathologies in the spinal cord of Npc1 mutant mice.
abstract: Niemann-Pick disease type C1 (NPC1) is a neurodegenerative disease with various progressive pathological features, for example, neuronal loss, dysmyelination, abnormal axon swelling, and gliosis, in the brain. Pathological activation of p38-mitogen-activated protein kinase (MAPK) results in hyperphosphorylation of tau protein, which contributes to the development of neurodegenerative diseases. In this study, axonal varicosities or spheroids and presynaptic aggregates in the spinal cord of the Npc1 mutant mice were found from postnatal day (P) 35 onwards, as indicated by the increased hyperphosphorylated neurofilament and synaptophysin immunoreactivity as well as the findings from electron microscopy. However, activities of astrocytes and microglia in the Npc1 mutant spinal cord were progressively increased earlier from P10 onwards, accompanied by increased expression of interleukin-1β and apolipoprotein E, as well as up-regulated p38-MAPK activity and enhanced phosphorylated tau protein, but not cyclin-dependent kinase 5/p35 complex and glycogen synthase kinase-3β. Taken together, our data suggest that the axonal pathologies in the Npc1 mutant spinal cord are strongly correlated with the increase of activated glial cells, which produce IL-1β and ApoE, resulting in the activation of p38-MAPK signaling pathway and enhanced phosphorylated tau protein.
authors.affiliation: Albrecht-Kossel-Institute for Neuroregeneration, Rostock University Medical Center, University of Rostock, Rostock, Germany.
authors.forename: Xin
authors.initials: X
authors.lastname: Yan
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.forename: Jan
authors.initials: J
authors.lastname: Lukas
authors.forename: Martin
authors.initials: M
authors.lastname: Witt
authors.forename: Andreas
authors.initials: A
authors.lastname: Wree
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
authors.forename: Jiankai
authors.initials: J
authors.lastname: Luo
mesh_terms: D000367:Age Factors; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D001369:Axons / Q000473:pathology / Q000502:physiology*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D053583:Interleukin-1beta / Q000378:metabolism; D007382:Intermediate Filaments / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000473:pathology / Q000503:physiopathology*; D009457:Neuroglia / Q000473:pathology / Q000502:physiology*; D000077296:Niemann-Pick C1 Protein; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology*; D016708:Synaptophysin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C492236:Cdk5r1 protein, mouse; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; C558298:Mapt protein, mouse; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D016708:Synaptophysin; C569015:Syp protein, mouse; D016875:tau Proteins; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C495906:Cdk5 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3
keywords: ApoE; IL-1β; Npc1; astrocytes; microglia; neurodegeneration; p38-MAPK