Tai, JBC, 2013.pdf (1.72 MB)
Levels of soluble apolipoprotein E/amyloid-β complex are reduced and oligomeric Aβ increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples
journal contributionposted on 2014-04-15, 00:00 authored by Leon M. Tai, Tina Bilousova, Lisa Jungbauer, Stephen K. Roeske, Katherine L. Youmans, Chunjiang Yu, Wayne W. Poon, Lindsey B. Cornwell, Carol A. Miller, Harry V. Vinters, Linda J. Van Eldik, David W. Fardo, Steve Estus, Guojun Bu, Karen Hoppens Gylys, Mary Jo LaDu
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.
This work was supported, in whole or in part, by National Institutes of Health Grants P01AG030128 (through the NIA) (to M.J.L. and S.E.), AG27465 (to KHG), and by AG18879 (to CAM); Alzheimer’s Association Grant ZEN-08- 899000 (to M.J.L.); University of Illinois at Chicago Center for Clinical and Translational Science Grant UL1RR029879 (to M.J.L.); and an Alzheimer’s drug discovery foundation grant (M.J.L and S.E). HVV is supported by the Daljit S. and Elaine Sarkaria Chair in Diagnostic Medicine.
Publisher StatementThis research was originally published in Journal of Biological Chemistry. Tai LM, Bilousova T, Jungbauer L, Roeske SK, Youmans KL, Yu C, Poon WW, Cornwell LB, Miller CA, Vinters HV, Van Eldik LJ, Fardo DW, Estus S, Bu G, Gylys KH, Ladu MJ. 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. Journal of Biological Chemistry. 2013 Feb 22;288(8):5914-26. © the American Society for Biochemistry and Molecular Biology
PublisherAmerican Society for Biochemistry and Molecular Biology