Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance

Topic: Brain proteins, microglia and lab models

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, amyloidogenic processing of amyloid precursor protein and Aβ 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 Aβ from the brain, suggesting that Aβ clearance pathways may be useful therapeutic targets for AD prevention.

Why it matters

In cognitively normal people, markers of amyloid build-up in the brain varied by apoE type, and in mice carrying human apoE versions, the clearance of soluble amyloid-β from the brain depended on which version was present, while amyloid production did not differ in young mice. The authors suggest APOE variants affect Alzheimer's risk by changing how amyloid-β is cleared, making clearance pathways possible targets for prevention.

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Read the original

• DOI: 10.1126/scitranslmed.3002156
• PubMed: 21715678
• Original source →
• Free full text: PubMed Central →

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@article{castellano2011-21715678,
  author  = {Castellano, Joseph M. and Kim, Jungsu and Stewart, Floy R. and Jiang, Hong and Demattos, Ronald Bradley and Patterson, Bruce W. and Fagan, Anne M. and Morris, John C. and Mawuenyega, Kwasi G. and Cruchaga, Carlos C and Goate, Alison and Bales, Kelly R. and Paul, Steven M. and Bateman, Randall John and Holtzman, David M.},
  title   = {{Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance}},
  journal = {Science Translational Medicine},
  year    = {2011},
  doi     = {10.1126/scitranslmed.3002156},
  pmid    = {21715678},
  url     = {https://doi.org/10.1126/scitranslmed.3002156}
}

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