Human apoE isoforms differentially regulate brain amyloid-ß peptide clearance.
Sci Transl Med
; 3(89): 89ra57, 2011 Jun 29.
Article
em En
| MEDLINE
| ID: mdl-21715678
ABSTRACT
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-ß (Aß) 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 Aß(42) peptide. However, the mechanism by which APOE alleles differentially modulate Aß 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 Aß deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aß clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aß accumulation later in life. Performing in vivo microdialysis in a mouse model of Aß-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aß in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aß deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Aß metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Aß deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and Aß 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 Aß from the brain, suggesting that Aß clearance pathways may be useful therapeutic targets for AD prevention.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Encéfalo
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Peptídeos beta-Amiloides
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Isoformas de Proteínas
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Apolipoproteína E4
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Sci Transl Med
Assunto da revista:
CIENCIA
/
MEDICINA
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos