Selective Deletion of Apolipoprotein E in Astrocytes Ameliorates the Spatial Learning and Memory Deficits in Alzheimer’s Disease (APP/PS1) mice by Inhibiting TGF-β/Smad2/STAT3 Signaling

Publication date: Available online 11 March 2017
Source:Neurobiology of Aging
Author(s): Jin-yu Zheng, Jian Sun, Chun-mei Ji, Lin Shen, Zhong-jun Chen, Peng Xie, Yuan-zhao Sun, Ru-tong Yu
Astrocytes and apolipoprotein E (apoE) play critical roles in cognitive function, not only under physiological conditions but also in some pathological situations, particularly in the pathological progression of Alzheimer's disease (AD). The regulatory mechanisms underlying the effect of apoE, derived from astrocytes, on cognitive deficits during AD pathology development are unclear. In this study, we generated APP/apoE^KO and APP/GFAP-apoE^KO mice (the AD mice model used in this study was based on the APP-FAD overexpression) to investigate the role of apoE, derived from astrocytes, in AD pathology and cognitive function. To explore the mechanism, we investigated the amyloidogenic process related TGF-β/Smad2/STAT3 signaling pathway and further confirmed by administering TGF-β-overexpression AAV (specific to astrocytes) to APP/GFAP-apoE^KO mice and TGF-β-inhibition AAV (specific to astrocytes) to APP/WT mice. Whole body deletion of apoE significantly ameliorated the spatial learning and memory impairment, reduced Aβ production and inhibited astrogliosis in APP/apoE^KO mice, as well as specific deletion apoE in astrocytes in APP/GFAP-apoE^KO mice. Moreover, Aβ accumulation was increased due to promotion of amyloidogenesis of APP, and astrogliosis was upregulated by activation of TGF-β/Smad2/STAT3 signaling. Furthermore, the overexpression of TGF-β in astrocytes in APP/GFAP-apoE^KO mice abrogated the effects of apoE knockout. In contrast, repression of TGF-β in astrocytes of APP/WT mice exerted a therapeutic effect similar to apoE knockout. These data suggested that apoE derived from astrocytes contributes to the risk of AD through TGF-β/Smad2/STAT3 signaling activation. These findings enhance our understanding of the role of apoE, derived from astrocytes, in AD and suggest it to be a potential biomarker and therapeutic target for AD.



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