title: The participation of insulin-like growth factor-binding protein 3 released by astrocytes in the pathology of Alzheimer's disease.
abstract: BACKGROUND
  Alzheimer's disease (AD) is characterized by senile plaques, extracellular deposits composed primarily of amyloid-beta (Aβ), and neurofibrillary tangles, which are abnormal intracellular inclusions containing hyperphosphorylated tau. The amyloid cascade hypothesis posits that the deposition of Aβ in the brain parenchyma initiates a sequence of events that leads to dementia. However, the molecular process by which the extracellular accumulation of Aβ peptides promotes intracellular pathologic changes in tau filaments remains unclear. To elucidate this process, we presumed that astrocytes might trigger neuronal reactions, leading to tau phosphorylation. In this study, we examined AD pathology from the perspective of the astrocyte-neuron interaction.
  
  
  RESULTS
  A cytokine-array analysis revealed that Aβ stimulates astrocytes to release several chemical mediators that are primarily related to inflammation and cell adhesion. Among those mediators, insulin-like growth factor (IGF)-binding protein 3 (IGFBP-3) was highly upregulated. In AD brains, the expression of IGFBP-3 was found to be increased by western blot analysis, and increased expression of IGFBP-3 was observed in astrocytes via fluorescence microscopy. In addition, we reproduced the increase in IGFBP-3 after treatment with Aβ using human astrocytoma cell lines and found that IGFBP-3 was expressed via calcineurin. In AD brains, the activated forms of calcineurin were found to be increased by western blot analysis, and increased expression of calcineurin was observed in astrocytes via fluorescence microscopy. When Ser9 of glycogen synthase kinase-3β (GSK-3β) is phosphorylated, GSK-3β is controlled and tau phosphorylation is suppressed. Aβ suppresses the phosphorylation of GSK-3β, leading to tau phosphorylation. In this study, we found that IGF-Ι suppressed tau phosphorylation induced by Aβ, although IGFBP-3 inhibited this property of IGF-Ι. As a result, IGFBP-3 contributed to tau phosphorylation and cell death induced by Aβ.
  
  
  CONCLUSIONS
  Our study suggested that calcineurin in astrocytes was activated by Aβ, leading to IGFBP-3 release. We further demonstrated that IGFBP-3 produced by astrocytes induced tau phosphorylation in neurons. Our study provides novel insights into the role of astrocytes in the induction of tau phosphorylation and suggests that IGFBP-3 could be an important link between Aβ and tau pathology and an important therapeutic target.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. kiwatana@kuhp.kyoto-u.ac.jp.
authors.forename: Kiwamu
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. ueken@kuhp.kyoto-u.ac.jp.
authors.forename: Kengo
authors.initials: K
authors.lastname: Uemura
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. mutsugi@kuhp.kyoto-u.ac.jp.|School of Human Health Sciences Faculty of Medicine, Kyoto University, Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. mutsugi@kuhp.kyoto-u.ac.jp.
authors.forename: Megumi
authors.initials: M
authors.lastname: Asada
authors.affiliation: School of Human Health Sciences Faculty of Medicine, Kyoto University, Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. maesako.masato.27r@st.kyoto-u.ac.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Maesako
authors.affiliation: Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan. akiyama-hr@igakuken.or.jp.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Department of Neurology, Sapporo Medical University School of Medicine, 16 Minami-1-jyo-Nishi, Chuo-ku, Sapporo, 060-8543, Japan. shimoha@sapmed.ac.jp.
authors.forename: Shun
authors.initials: S
authors.lastname: Shimohama
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan. ryosuket@kuhp.kyoto-u.ac.jp.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: School of Human Health Sciences Faculty of Medicine, Kyoto University, Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. kinoshita.ayae.6v@kyoto-u.ac.jp.
authors.forename: Ayae
authors.initials: A
authors.lastname: Kinoshita
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001254:Astrocytoma / Q000235:genetics / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019703:Calcineurin / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D003470:Culture Media; D018972:Insulin-Like Growth Factor Binding Protein 3; D012333:RNA, Messenger; D016875:tau Proteins; D007334:Insulin-Like Growth Factor I; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D019703:Calcineurin; D016559:Tacrolimus