title: Human ApoE ɛ2 Promotes Regulatory Mechanisms of Bioenergetic and Synaptic Function in Female Brain: A Focus on V-type H+-ATPase.
abstract: Humans possess three major isoforms of the apolipoprotein E (ApoE) gene encoded by three alleles: ApoE ɛ2 (ApoE2), ApoE ɛ3 (ApoE3), and ApoE ɛ4 (ApoE4). It is established that the three ApoE isoforms confer differential susceptibility to Alzheimer's disease (AD); however, an in-depth molecular understanding of the underlying mechanisms is currently unavailable. In this study, we examined the cortical proteome differences among the three ApoE isoforms using 6-month-old female, human ApoE2, ApoE3, and ApoE4 gene-targeted replacement mice and two-dimensional proteomic analyses. The results reveal that the three ApoE brains differ primarily in two areas: cellular bioenergetics and synaptic transmission. Of particular significance, we show for the first time that the three ApoE brains differentially express a key component of the catalytic domain of the V-type H+-ATPase (Atp6v), a proton pump that mediates the concentration of neurotransmitters into synaptic vesicles and thus is crucial in synaptic transmission. Specifically, our data demonstrate that ApoE2 brain exhibits significantly higher levels of the B subunit of Atp6v (Atp6v1B2) when compared to both ApoE3 and ApoE4 brains, with ApoE4 brain exhibiting the lowest expression. Our additional analyses show that Atp6v1B2 is significantly impacted by aging and AD pathology and the data suggest that Atp6v1B2 deficiency could be involved in the progressive loss of synaptic integrity during early development of AD. Collectively, our findings indicate that human ApoE isoforms differentially modulate regulatory mechanisms of bioenergetic and synaptic function in female brain. A more efficient and robust status in both areas-in which Atp6v may play a role-could serve as a potential mechanism contributing to the neuroprotective and cognition-favoring properties associated with the ApoE2 genotype.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Woody
authors.affiliation: Obstetrics and Gynecology Department, University of Kansas School of Medicine, Kansas City, KS, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors.forename: Shaher
authors.initials: S
authors.lastname: Ibrahimi
authors.affiliation: Obstetrics and Gynecology Department, University of Kansas School of Medicine, Kansas City, KS, USA.|Pathology and Laboratory Department, University of Kansas School of Medicine, Kansas City, KS, USA.
authors.forename: Yafeng
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA.|Neuroscience Graduate Program, University of Kansas, Lawrence, KS, USA.
authors.forename: Liqin
authors.initials: L
authors.lastname: Zhao
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D058227:Amyloidogenic Proteins / Q000378:metabolism; D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000473:pathology / Q000648:ultrastructure; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*
chemical_list: D058227:Amyloidogenic Proteins; D053329:Apolipoprotein E2; D053327:Apolipoprotein E4; D025262:Vacuolar Proton-Translocating ATPases
keywords: Alzheimer’s disease; ApoE2; ApoE3; ApoE4; V-type H+-ATPase; cellular bioenergetics; synaptic transmission