title: Early-life stress leads to impaired spatial learning and memory in middle-aged ApoE4-TR mice.
abstract: Apolipoprotein E (ApoE) is a major lipid carrier that supports lipid transport and injury repair in the brain. The APOE ε4 allele is associated with depression, mild cognitive impairment (MCI) and dementia; however, the precise molecular mechanism through which ApoE4 influences the risk of disease development remains unknown. To address this gap in knowledge, we investigated the potential effects of chronic unpredictable mild stress (CUMS) on ApoE3 and ApoE4 target replacement (ApoE3-TR and ApoE4-TR) mice.
  
  
  
  All ApoE-TR mice exposed to CUMS at 3 months old recovered from a depression-like state by the age of 12 months. Of note, ApoE4-TR mice, unlike age-matched ApoE3-TR mice, displayed impaired spatial cognitive abilities, loss of GABAergic neurons, decreased expression of Reelin, PSD95, SYN and Fyn, and reduced phosphorylation of NMDAR2B and CREB.
  
  
  
  These results suggest that early-life stress may mediate cognitive impairment in middle-age ApoE4-TR mice through sustained reduction of GABAergic neurons and Reelin expression, which might further diminish the activation of the Fyn/NMDAR2B signaling pathway.
authors.affiliation: Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.|Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
authors.forename: Lan-Yan
authors.initials: LY
authors.lastname: Lin
authors.affiliation: Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.|Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.|Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
authors.forename: Xiao-Man
authors.initials: XM
authors.lastname: Dai
authors.affiliation: Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
authors.forename: Nai-An
authors.initials: NA
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
authors.forename: Xi-Lin
authors.initials: XL
authors.lastname: Wu
authors.affiliation: Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Fang
authors.affiliation: Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.|Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China.
authors.forename: Yuan-Gui
authors.initials: YG
authors.lastname: Zhu
authors.affiliation: Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China. chenxc998@163.com.|Key Laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, 29 Xinquan Road, Fuzhou, 350001, China. chenxc998@163.com.|Department of Neurology, Affiliated Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian, 350001, People's Republic of China. chenxc998@163.com.
authors.forename: Xiao-Chun
authors.initials: XC
authors.lastname: Chen
mesh_terms: D000375:Aging; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics* / Q000378:metabolism; D003704:Dementia / Q000378:metabolism*; D006801:Humans; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D000091042:Reelin Protein; D065853:Spatial Learning / Q000502:physiology*; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: D053327:Apolipoprotein E4; D000091042:Reelin Protein; C000717127:RELN protein, human; C000717128:Reln protein, mouse
keywords: Apolipoprotein E genotype; CUMS; Cognitive impairment; Major depressive disorder; Reelin