Journal
GLIA
Volume 64, Issue 2, Pages 240-254Publisher
WILEY
DOI: 10.1002/glia.22926
Keywords
astrocyte; fluoxetine; Alzheimer's disease (AD); astrocyte conditioned medium (ACM); beta-amyloid
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Funding
- Manitoba Health Research Council Foundation
- Canadian Institute of Health Research (CIHR)
- Health Sciences Centre Foundation
- National Natural Science Foundation of China [81501187]
- Anhui Provincial Natural Science Foundation [1508085QH173]
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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 beta-amyloid (A beta) 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 A beta 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.
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