title: Golgin-84-associated Golgi fragmentation triggers tau hyperphosphorylation by activation of cyclin-dependent kinase-5 and extracellular signal-regulated kinase.
abstract: Tau hyperphosphorylation is a critical event in Alzheimer's disease, in which the neuronal Golgi fragmentation occurs earlier than tau hyperphosphorylation. However, the intrinsic link between Golgi impairment and tau pathology is missing. By electron microscopy and western blotting, we observed in the present study that the neuronal Golgi fragmentation was increased age-dependently with a correlated tau hyperphosphorylation in the brains of C57BL/6 mice aged from 4 to 16 months. Simultaneously, golgin-84 and Golgi reassembly stacking protein 65, 2 important Golgi matrix proteins, were decreased in the brains of elder mice. Further studies in HEK293/tau cells showed that Golgi-disturbing agents, brefeldin A and nocodazole induced tau hyperphosphorylation. Knockdown of golgin-84, not Golgi reassembly stacking protein 65, by small interfering RNA was sufficient to induce tau hyperphosphorylation, while over-expressing golgin-84 arrested the brefeldin A-induced Golgi fragmentation and tau hyperphosphorylation. Finally, we demonstrated that cyclin-dependent kinase-5 and extracellular signal-regulated kinase were activated after golgin-84 knockdown, and simultaneous inhibition of these kinases abolished the golgin-84 deficit-induced tau hyperphosphorylation. These data suggest Golgi fragmentation could be an upstream event triggering tau hyperphosphorylation through golgin-84 deficit-induced activation of cyclin-dependent kinase-5 and extracellular signal-regulated kinase.
authors.affiliation: Department of Pathology and Pathophysiology, Ultrastructural Pathology Center, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Present address: Department of Dermatology, The First Hospital of Wuhan, Wuhan, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Department of Pathology and Pathophysiology, Ultrastructural Pathology Center, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology and Pathophysiology, Ultrastructural Pathology Center, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Pathology and Pathophysiology, Ultrastructural Pathology Center, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pathology and Pathophysiology, Ultrastructural Pathology Center, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Niu
authors.affiliation: Department of Pathology and Pathophysiology, Ultrastructural Pathology Center, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Pathology and Pathophysiology, Ultrastructural Pathology Center, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Wei
authors.affiliation: Department of Pathology and Pathophysiology, Ultrastructural Pathology Center, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Pathology and Pathophysiology, Ultrastructural Pathology Center, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Chu
authors.affiliation: Department of Pathology and Pathophysiology, Ultrastructural Pathology Center, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pathology and Pathophysiology, Ultrastructural Pathology Center, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pathology and Pathophysiology, Ultrastructural Pathology Center, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Pei
authors.affiliation: Department of Pathology and Pathophysiology, Ultrastructural Pathology Center, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: wangjz@mail.hust.edu.cn.
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.affiliation: Department of Pathology and Pathophysiology, Ultrastructural Pathology Center, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: tianq@hust.edu.cn.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006056:Golgi Apparatus / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000077614:Golgi Matrix Proteins; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000235:genetics; D033921:Vesicular Transport Proteins; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C060042:GOLGA5 protein, human; D000077614:Golgi Matrix Proteins; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Alzheimer's disease; Golgi fragmentation; Golgin-84; Tau