Human apoE isoforms differentially regulate brain amyloid-? peptide clearance.

ABSTRACT: The apolipoprotein E (APOE) ?4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE ?4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-? (A?) peptide. In contrast, the APOE ?2 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 A?(42) peptide. However, the mechanism by which APOE alleles differentially modulate A? 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 A? deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect A? clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of A? accumulation later in life. Performing in vivo microdialysis in a mouse model of A?-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble A? in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of A? deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble A? metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of A? deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and A? 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 A? from the brain, suggesting that A? clearance pathways may be useful therapeutic targets for AD prevention.

SUBMITTER: Castellano JM 

PROVIDER: S-EPMC3192364 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature