Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance

作者：Joseph M. Castellano, Jungsu Kim, Floy R. Stewart, Hong Jiang, Ronald B. DeMattos, Bruce W. Patterson, Anne M. Fagan, John C. Morris, Kwasi G. Mawuenyega, Carlos Cruchaga, Alison Goate, Kelly R. Bales, Steven M. Paul, Randall J. Bateman, David M. Holtzman · 发表于：Science Translational Medicine · 年份：2011 · DOI：10.1126/scitranslmed.3002156 · 被引用次数：1209 · 研究领域：Alzheimer's disease research and treatments、Neuroscience and Neuropharmacology Research、Peroxisome Proliferator-Activated Receptors

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE ε4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. In contrast, the APOE ε2 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 Aβ(42) peptide. However, the mechanism by which APOE alleles differentially modulate Aβ 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 Aβ deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aβ clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aβ accumulation later in life. Performing in vivo microdialysis in a mouse model of Aβ-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aβ in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aβ deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Aβ metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Aβ deposition in amyloid plaques in the brain. Additionally...