title: Regulation of astrocyte pathology by fluoxetine prevents the deterioration of Alzheimer phenotypes in an APP/PS1 mouse model.
abstract: Studies have implicated astrocytic dysfunction in Alzheimer's disease (AD). However, the role of astrocytes in the pathophysiology and treatment of the disease is poorly characterized. Here, we identified astrocytes as independent key factors involved in several Alzheimer-like phenotypes in an APP/PS1 mouse model, including amyloid pathology, altered neuronal and synaptic properties, and impaired cognition. In vitro astrocytes from APP/PS1 mice induced synaptotoxicity as well as reduced dendritic complexity and axonal branching of hippocampal neurons. These astrocytes produced high levels of soluble β-amyloid (Aβ) which could be significantly inhibited by fluoxetine (FLX) via activating serotonin 5-HT2 receptors. FLX could also protect hippocampal neurons against astrocyte-induced neuronal damage in vitro. In the same APP/PS1 mice, FLX inhibited activation of astrocytes, lowered Aβ products, ameliorated neurotoxicity, and improved behavioral performance. These findings may provide a basis for the clinical application of FLX in patients, and may also lay the groundwork for exploration of other novel astrocyte-based therapies of AD.
authors.affiliation: Mental Health Center, Shantou University, Shantou, Guangdong, People's Republic of China.|Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China.|Department of Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Jinping
authors.initials: J
authors.lastname: Qiao
authors.affiliation: Mental Health Center, Shantou University, Shantou, Guangdong, People's Republic of China.|Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Junhui
authors.initials: J
authors.lastname: Wang
authors.affiliation: Beijing Anding Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Shenghua
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Abulimiti
authors.initials: A
authors.lastname: Adilijiang
authors.affiliation: Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Huining
authors.initials: H
authors.lastname: Guo
authors.affiliation: Department of Psychiatry, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shanxi, People's Republic of China.
authors.forename: Ruiguo
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Beijing Anding Hospital, Capital Medical University, Beijing, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Neurology, First Affiliated Hospital of Henan University, Henan, People's Republic of China.
authors.forename: Gang
authors.initials: G
authors.lastname: Luo
authors.affiliation: Department of Neurosurgery, Shanghai Changhai Hospital, Secondary Military Medical University, Shanghai, People's Republic of China.
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Mental Health Center, Shantou University, Shantou, Guangdong, People's Republic of China.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Jiming
authors.initials: J
authors.lastname: Kong
authors.affiliation: Mental Health Center, Shantou University, Shantou, Guangdong, People's Republic of China.
authors.forename: Qingjun
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Xin-Min
authors.initials: XM
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000494:pharmacology*; D006801:Humans; D018782:Maze Learning; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D044348:Receptors, Serotonin, 5-HT2; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005473:Fluoxetine
keywords: Alzheimer's disease (AD); astrocyte; astrocyte conditioned medium (ACM); beta-amyloid; fluoxetine