title: Cumulative effects of the ApoE genotype and gender on the synaptic proteome and oxidative stress in the mouse brain.
abstract: Elderly females, particularly those carrying the apolipoprotein E (ApoE)-ε4 allele, have a higher risk of developing Alzheimer's disease (AD). However, the underlying mechanism for this increased susceptibility remains unclear. In this study, we investigated the effects of the ApoE genotype and gender on the proteome of synaptosomes. We isolated synaptosomes and used label-free quantitative proteomics, to report, for the first time, that the synaptosomal proteomic profiles in the cortex of female human-ApoE4 mice exhibited significantly reduced expression of proteins related to energy metabolism, which was accompanied by increased levels of oxidative stress. In addition, we also first demonstrated that the proteomic response in synaptic termini was more susceptible than that in the soma to the adverse effects induced by genders and genotypes. This suggests that synaptic mitochondria might be 'older' than mitochondria in the soma of neurons; therefore, they might contain increased cumulative damage from oxidative stress. Furthermore, female human-ApoE4 mice had much lower oestrogen levels in the cortex and treatment with oestrogen protected ApoE3 stable transfected C6 neurons from oxidative stress. Overall, this study reveals complex ApoE- and gender-dependent effects on synaptic function and also provides a basis for future studies of candidates based on specific pathways involved in the pathogenesis of AD. The lack of oestrogen-mediated protection regulated by the ApoE genotype led to synaptic mitochondrial dysfunction and increased oxidative stress, which might make older females more susceptible to AD.
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases,School of Life Science, University of Science and Technology of China,Hefei 230027, Anhui,China.
authors.forename: Lv
authors.initials: L
authors.lastname: Shi
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases,School of Life Science, University of Science and Technology of China,Hefei 230027, Anhui,China.
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases,School of Life Science, University of Science and Technology of China,Hefei 230027, Anhui,China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases,School of Life Science, University of Science and Technology of China,Hefei 230027, Anhui,China.
authors.forename: Changlu
authors.initials: C
authors.lastname: Tao
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases,School of Life Science, University of Science and Technology of China,Hefei 230027, Anhui,China.
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Liu
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases,School of Life Science, University of Science and Technology of China,Hefei 230027, Anhui,China.
authors.forename: Fantao
authors.initials: F
authors.lastname: Meng
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases,School of Life Science, University of Science and Technology of China,Hefei 230027, Anhui,China.
authors.forename: Gao
authors.initials: G
authors.lastname: Wu
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases,School of Life Science, University of Science and Technology of China,Hefei 230027, Anhui,China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases,School of Life Science, University of Science and Technology of China,Hefei 230027, Anhui,China.
authors.forename: Chun
authors.initials: C
authors.lastname: Xia
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases,School of Life Science, University of Science and Technology of China,Hefei 230027, Anhui,China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases,School of Life Science, University of Science and Technology of China,Hefei 230027, Anhui,China.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Bi
authors.affiliation: CAS Key Laboratory of Brain Function and Diseases,School of Life Science, University of Science and Technology of China,Hefei 230027, Anhui,China.
authors.forename: Jiang-Ning
authors.initials: JN
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D019062:Cell Adhesion Molecules, Neuron-Glia / Q000378:metabolism; D002540:Cerebral Cortex / Q000648:ultrastructure*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D057907:Post-Synaptic Density / Q000378:metabolism / Q000648:ultrastructure; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D012727:Sex Characteristics; D013574:Synaptosomes / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D001057:Apolipoproteins E; D019062:Cell Adhesion Molecules, Neuron-Glia; D004967:Estrogens; D020543:Proteome; D008315:Malondialdehyde; D005978:Glutathione; D019803:Glutathione Disulfide