Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance

Human apoE4 increases the concentration of soluble Aβ in the brain by impairing its clearance. Clearing the Debris in Alzheimer’s Disease The strongest risk factor for developing the common sporadic form of Alzheimer’s disease (AD) that occurs in old age is the ε4 allele encoding apolipoprotein E4 (apoE4). Two ε4 alleles can lower the age of onset of AD by 10 to 15 years. In contrast, the ε2 allele decreases the risk of developing this neurodegenerative disorder. APOE is important for lipoprotein metabolism, but how it might be involved in AD has remained unclear. It has been suggested that the apoE4 isoform might somehow help to drive accumulation of the peptide amyloid-β (Aβ), which forms amyloid plaques in the brain that contribute to neuronal death and are the characteristic hallmark of AD. In a tour de force study in humans and mice, Holtzman and his team at Washington University in St. Louis now show that apoE4 contributes to Aβ accumulation in the brain not by affecting Aβ synthesis but by affecting its clearance. First, the authors looked at the Aβ concentration in the cerebrospinal fluid (CSF) of cognitively normal individuals under age 70 carrying different APOE genotypes. They found that those with the ε4/ε4 genotype had a much lower CSF Aβ concentration than did those with the protective ε2/ε3 genotype. A CSF Aβ concentration of less than 500 pg/ml is an indication that Aβ peptide is accumulating in the brain and thus is not moving into the CSF. Next, the researchers analyzed imaging data using a dye called Pittsburgh compound B that binds to amyloid plaques in the brain and showed that those individuals with the ε4/ε4 genotype bound more dye than did those with the other APOE genotypes. They then moved to a mouse model of AD in which the mice expressed one of the three human apoE isoforms. They measured Aβ concentrations in the interstitial fluid of these mice using in vivo microdialysis and then looked at stained hippocampal sections from these mice. They found greater Aβ concentrations in both interstitial fluid and the hippocampus in mice expressing the human apoE4 isoform than in animals expressing either the E3 or E2 isoforms. They discovered that this difference in Aβ concentration between the mice carrying different APOE genotypes was present in young as well as aged mice, suggesting that it predates the appearance of amyloid plaques. They then measured clearance of Aβ from the interstitial fluid of young mice and showed that those with the human apoE4 isoform were less able to clear Aβ than those with the apoE2 or apoE3 isoforms. The researchers showed that processing of the amyloid precursor protein and generation of the Aβ peptide did not vary according to genotype, lending credence to the hypothesis that apoE4 affects clearance of Aβ but not its synthesis. This thorough study sheds new light on how apoE4 is implicated in AD and highlights the Aβ clearance pathway as a new target for developing drugs to slow or even halt the accumulation of amyloid plaques in patients with AD. 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 Aβ42 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.