title: 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.
abstract: 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/apoEKO) and APP/glial fibrillary acidic protein (GFAP)-apoEKOmice (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 β/mothers against decapentaplegic homolog 2/signal transducer and activator of transcription 3 (TGF-β/Smad2/STAT3) signaling pathway and further confirmed by administering TGF-β-overexpression adeno-associated virus (specific to astrocytes) to APP/GFAP-apoEKOmice and TGF-β-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 β-protein production and inhibited astrogliosis in APP/apoEKOmice, as well as specific deletion apoE in astrocytes in APP/GFAP-apoEKOmice. Moreover, amyloid β-protein 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-apoEKOmice 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.
authors.affiliation: Department of Neurosurgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, P. R. China; Department of Neurosurgery, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China.
authors.forename: Jin-Yu
authors.initials: JY
authors.lastname: Zheng
authors.affiliation: Department of Anesthesiology, Huai'an Maternal and Child Health Hospital, Huai'an, Jiangsu, P. R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, P. R. China.
authors.forename: Chun-Mei
authors.initials: CM
authors.lastname: Ji
authors.affiliation: Department of Neurosurgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, P. R. China.
authors.forename: Lin
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Neurosurgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, P. R. China.
authors.forename: Zhong-Jun
authors.initials: ZJ
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, P. R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Xie
authors.affiliation: Department of Neurosurgery, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu, P. R. China.
authors.forename: Yuan-Zhao
authors.initials: YZ
authors.lastname: Sun
authors.affiliation: Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China; Laboratory of Neurosurgery, Xuzhou Medical University, Xuzhou, Jiangsu, P. R. China. Electronic address: rutong_yu@163.com.
authors.forename: Ru-Tong
authors.initials: RT
authors.lastname: Yu
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000523:psychology*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000502:physiology*; D001253:Astrocytes / Q000502:physiology*; D004195:Disease Models, Animal; D017353:Gene Deletion; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics*; D008822:Mice, Transgenic; D050796:STAT3 Transcription Factor / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics*; D051899:Smad2 Protein / Q000502:physiology*; D065853:Spatial Learning / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D001057:Apolipoproteins E; D050796:STAT3 Transcription Factor; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; C494087:Stat3 protein, mouse; D016212:Transforming Growth Factor beta
keywords: Alzheimer's disease; ApoE; Astrocytes; Aβ; Knockout