Regulation of astrocyte pathology by fluoxetine prevents the deterioration of Alzheimer phenotypes in an APP/PS1 mouse model |
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| Authors: | Hongxing Wang Yanbo Zhang Shenghua Zhu Abulimiti Adilijiang Huining Guo Ruiguo Zhang Wei Guo Gang Luo Yiqing Qiu Haiyun Xu Jiming Kong Qingjun Huang Xin‐Min Li |
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| Affiliation: | 1. Beijing Anding Hospital, Capital Medical University, Beijing, People's Republic of China;2. Department of Psychiatry, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada;3. Department of Anatomy and Cell Science, University of Manitoba, Winnipeg, Manitoba, Canada;4. Department of Psychiatry, University of Alberta, Edmonton, Alberta, Canada;5. Department of Psychiatry, Xijing Hospital, the Fourth Military Medical University, Xi'an, Shanxi, People's Republic of China;6. Department of Neurology, First Affiliated Hospital of Henan University, Henan, People's Republic of China;7. Department of Neurosurgery, Shanghai Changhai Hospital, Secondary Military Medical University, Shanghai, People's Republic of China;8. Mental Health Center, Shantou University, Shantou, Guangdong, People's Republic of China |
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| 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. GLIA 2016;64:240–254 |
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| Keywords: | astrocyte fluoxetine Alzheimer's disease (AD) astrocyte conditioned medium (ACM) beta‐amyloid |
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