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

来自 NCBI

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作者：

JM Castellano，J Kim，FR Stewart，H Jiang，DeMattos, R. B.，BW Patterson，AM Fagan，JC Morris，KG Mawuenyega，C Cruchaga

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摘要：

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.

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关键词：

Animals Mice, Inbred C57BL Humans Mice Brain Alzheimer Disease Microdialysis Biological Markers Genotype Apolipoprotein E4