Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 8, Pages 5914-5926Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.442103
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Funding
- National Institutes of Health from NIA [P01AG030128, AG27465, G18879, 050 AG05142, P50 AG 16970, P50 AG016573, P30 AG028383]
- Alzheimer's Association Grant [ZEN-08-899000]
- University of Illinois at Chicago Center for Clinical and Translational Science Grant [UL1RR029879]
- Alzheimer's Drug Discovery Foundation Grant
- Daljit S. and Elaine Sarkaria Chair in Diagnostic Medicine
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Human apolipoprotein E (apoE) isoforms may differentially modulate amyloid-beta (A beta) levels. Evidence suggests physical interactions between apoE and A beta are partially responsible for these functional effects. However, the apoE/A beta 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/A beta in a single, quantitative method and was used to address the hypothesis that reduced levels of soluble apoE/A beta and an increase in soluble A beta, specifically oligomeric A beta (oA beta), are associated with APOE4 and AD. Previously, soluble A beta 42 and oA beta 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/A beta levels were lower in E4FAD mice compared with E2FAD and E3FAD mice, thus providing evidence that apoE/A beta levels isoform-specifically modulate soluble oA beta clearance. Similar results were observed in soluble preparations of human cortical synaptosomes; apoE/A beta levels were lower in AD patients compared with controls and lower with APOE4 in the AD cohort. In human CSF, apoE/A beta levels were also lower in AD patients and with APOE4 in the AD cohort. Importantly, although total A beta 42 levels decreased in AD patients compared with controls, oA beta levels increased and were greater with APOE4 in the AD cohort. Overall, apoE isoform-specific formation of soluble apoE/A beta modulates oA beta levels, suggesting a basis for APOE4-induced AD risk and a mechanistic approach to AD biomarkers.
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