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 amyloid precursor protein/ apoE knockout (APP/apoE(KO)) and APP/glial fibrillary acidic protein (GFAP)-apoE(KO) mice (the AD mice model used in this study was based on the APP-familial Alzheimer disease 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 transforming growth factor beta/mothers against decapentaplegic homolog 2/signal transducer and activator of transcription 3 (TGF-beta/Smad2/STAT3) signaling pathway and further confirmed by administering TGF-beta-overexpression adeno-associated virus (specific to astrocytes) to APP/GFAP-apoEKO mice and TGF-beta-inhibition adeno-associated virus (specific to astrocytes) to APP/WT mice. Whole body deletion of apoE significantly ameliorated the spatial learning and memory impairment, reduced amyloid beta-protein production and inhibited astrogliosis in APP/apoE(KO) mice, as well as specific deletion apoE in astrocytes in APP/GFAP-apoE(KO) mice. Moreover, amyloid beta-protein accumulation was increased due to promotion of amyloidogenesis of APP,and astrogliosis was upregulated by activation of TGF-beta/Smad2/STAT3 signaling. Furthermore, the overexpression of TGF-beta in astrocytes in APP/GFAP-apoE(KO) mice abrogated the effects of apoE knockout. In contrast, repression of TGF-beta 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-beta/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. (C) 2017 Elsevier Inc. All rights reserved.