title: Levels of soluble apolipoprotein E/amyloid-β (Aβ) complex are reduced and oligomeric Aβ increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples.
abstract: Human apolipoprotein E (apoE) isoforms may differentially modulate amyloid-β (Aβ) levels. Evidence suggests physical interactions between apoE and Aβ are partially responsible for these functional effects. However, the apoE/Aβ complex is not a single static structure; rather, it is defined by detection methods. Thus, literature results are inconsistent and difficult to interpret. An ELISA was developed to measure soluble apoE/Aβ in a single, quantitative method and was used to address the hypothesis that reduced levels of soluble apoE/Aβ and an increase in soluble Aβ, specifically oligomeric Aβ (oAβ), are associated with APOE4 and AD. Previously, soluble Aβ42 and oAβ levels were greater with APOE4 compared with APOE2/APOE3 in hippocampal homogenates from EFAD transgenic mice (expressing five familial AD mutations and human apoE isoforms). In this study, soluble apoE/Aβ levels were lower in E4FAD mice compared with E2FAD and E3FAD mice, thus providing evidence that apoE/Aβ levels isoform-specifically modulate soluble oAβ clearance. Similar results were observed in soluble preparations of human cortical synaptosomes; apoE/Aβ levels were lower in AD patients compared with controls and lower with APOE4 in the AD cohort. In human CSF, apoE/Aβ levels were also lower in AD patients and with APOE4 in the AD cohort. Importantly, although total Aβ42 levels decreased in AD patients compared with controls, oAβ levels increased and were greater with APOE4 in the AD cohort. Overall, apoE isoform-specific formation of soluble apoE/Aβ modulates oAβ levels, suggesting a basis for APOE4-induced AD risk and a mechanistic approach to AD biomarkers.
authors.affiliation: Department of Anatomy and Cell Biology, University of Illinois, Chicago, Illinois 60612, USA.
authors.forename: Leon M
authors.initials: LM
authors.lastname: Tai
authors.forename: Tina
authors.initials: T
authors.lastname: Bilousova
authors.forename: Lisa
authors.initials: L
authors.lastname: Jungbauer
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Roeske
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Youmans
authors.forename: Chunjiang
authors.initials: C
authors.lastname: Yu
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Poon
authors.forename: Lindsey B
authors.initials: LB
authors.lastname: Cornwell
authors.forename: Carol A
authors.initials: CA
authors.lastname: Miller
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
authors.forename: David W
authors.initials: DW
authors.lastname: Fardo
authors.forename: Steve
authors.initials: S
authors.lastname: Estus
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: Karen Hoppens
authors.initials: KH
authors.lastname: Gylys
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Ladu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D001057:Apolipoproteins E / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D015331:Cohort Studies; D003433:Crosses, Genetic; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D020033:Protein Isoforms; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D015415:Biomarkers; D020033:Protein Isoforms