ApoE influences amyloid-? (A?) clearance despite minimal apoE/A? association in physiological conditions.

ABSTRACT: Apolipoprotein E gene (APOE) alleles may shift the onset of Alzheimer's disease (AD) through apoE protein isoforms changing the probability of amyloid-? (A?) accumulation. It has been proposed that differential physical interactions of apoE isoforms with soluble A? (sA?) in brain fluids influence the metabolism of A?, providing a mechanism to account for how APOE influences AD risk. In contrast, we provide clear evidence that apoE and sA? 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 sA? in fluid, we find that apoE isoforms regulate the metabolism of sA? by astrocytes and in the interstitial fluid of mice that received apoE infusions during brain A? microdialysis. We find that a significant portion of apoE and sA? 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 sA? metabolism despite minimal evidence of direct interactions in extracellular fluids. We propose that apoE influences sA? metabolism not through direct binding to sA? 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.

SUBMITTER: Verghese PB 

PROVIDER: S-EPMC3651443 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature