| First Author | Verghese PB | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 19 | Pages | E1807-16 |
| PubMed ID | 23620513 | Mgi Jnum | J:359709 |
| Mgi Id | MGI:6862303 | Doi | 10.1073/pnas.1220484110 |
| Citation | Verghese PB, et al. (2013) ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions. Proc Natl Acad Sci U S A 110(19):E1807-16 |
| abstractText | Apolipoprotein E gene (APOE) alleles may shift the onset of Alzheimer's disease (AD) through apoE protein isoforms changing the probability of amyloid-beta (Abeta) accumulation. It has been proposed that differential physical interactions of apoE isoforms with soluble Abeta (sAbeta) in brain fluids influence the metabolism of Abeta, providing a mechanism to account for how APOE influences AD risk. In contrast, we provide clear evidence that apoE and sAbeta interactions occur minimally in solution and in the cerebrospinal fluid of human subjects, producing apoE3 and apoE4 isoforms as assessed by multiple biochemical and analytical techniques. Despite minimal extracellular interactions with sAbeta in fluid, we find that apoE isoforms regulate the metabolism of sAbeta by astrocytes and in the interstitial fluid of mice that received apoE infusions during brain Abeta microdialysis. We find that a significant portion of apoE and sAbeta compete for the low-density lipoprotein receptor-related protein 1 (LRP1)-dependent cellular uptake pathway in astrocytes, providing a mechanism to account for apoE's regulation of sAbeta metabolism despite minimal evidence of direct interactions in extracellular fluids. We propose that apoE influences sAbeta metabolism not through direct binding to sAbeta in solution but through its actions with other interacting receptors/transporters and cell surfaces. These results provide an alternative frame work for the mechanistic explanations on how apoE isoforms influence the risk of AD pathogenesis. |
