| First Author | Castellano JM | Year | 2011 |
| Journal | Sci Transl Med | Volume | 3 |
| Issue | 89 | Pages | 89ra57 |
| PubMed ID | 21715678 | Mgi Jnum | J:178363 |
| Mgi Id | MGI:5298186 | Doi | 10.1126/scitranslmed.3002156 |
| Citation | Castellano JM, et al. (2011) Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 3(89):89ra57 |
| abstractText | The apolipoprotein E (APOE) epsilon4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE epsilon4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-beta (Abeta) peptide. In contrast, the APOE epsilon2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of Abeta(42) peptide. However, the mechanism by which APOE alleles differentially modulate Abeta accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral Abeta deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Abeta clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Abeta accumulation later in life. Performing in vivo microdialysis in a mouse model of Abeta-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Abeta in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Abeta deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Abeta metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Abeta deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and Abeta synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of Abeta from the brain, suggesting that Abeta clearance pathways may be useful therapeutic targets for AD prevention. |
