Human apoE isoforms differentially regulate brain amyloid-β peptide clearance

By Joseph M. Castellano, Jungsu Kim, F. Stewart, Hong Jiang, R. DeMattos, B. Patterson, Anne M. Fagan, John C. Morris, K. Mawuenyega, Carlos Cruchaga and 5 more. Science Translational Medicine, 2011

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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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/e501f9c7c6b1fad550f0272a61eb43df18830c86

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Citations in the corpus

Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders (2011, background): “All firmly established genetic risk factors for AD promote the buildup of A β , either by increasing its production, promoting its aggregation, or impeding its elimination 9, 13 .”
Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies (2016, background): “an increase in Aβ production, but with a reduced ability to clear Aβ from the brain [111,112].”
A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. (2017, neutral): “…mechanism, which critically involves reduction in the expression of homeostatic microglia checkpoint genes (e.g., Cx3cr1 and P2ry12/ P2ry13) and upregulation of genes such as B2m, Apoe (associated with AD progression) (Castellano et al., 2011), and the Trem2 adaptor Tyrobp (Figures 5 and 6).”
Alzheimer's disease risk genes and mechanisms of disease pathogenesis (2014, neutral): “The SNP rs9331888 is associated with expression of an alternative splice variant (36), whereas rs9331888 and rs11136000 are associated with plasma clusterin levels (47–49).”
The amyloid hypothesis of Alzheimer's disease at 25 years (2016, methodology): “A detailed quantitative study of Ab homeostasis using in vivo microdialysis in hAPP × hApoE crossed mice has shown that Ab clearance (but not Ab production) is decreased by ApoE4 > E3 > E2, closely paralleling the degree of Ab deposition in such mice (Castellano et al, 2011).”
Alzheimer’s disease: experimental models and reality (2017, background): “This is further complicated by the fact that expression of different isoforms of human ApoE in transgenic mice results in different levels of plaque and CAA burden with apoE4 expression enhancing amyloid deposition compared to apoE3 or apoE2 [3, 21, 40, 59, 86, 178].”
What is normal in normal aging? Effects of Aging, Amyloid and Alzheimer’s Disease on the Cerebral Cortex and the Hippocampus (2014, background): “clearance than increased production (DeMattos et al., 2004; Mawuenyega et al., 2010; Castellano et al., 2011), in contrast to”
The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes (2012, background): “Eisele, Y.S. et al. Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis.”
β-Amyloid accumulation in the human brain after one night of sleep deprivation (2018, background): “While we are interpreting our findings of increases in ABB after SD to reflect Aβ accumulation due to lack of glymphatic clearance (or other unknown mechanisms), we cannot rule out the possibility that they reflect increases in the synthesis of Aβ (38) from lack of sleep.”
Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. (2012, background): “Strong evidence suggests a major mechanism by which apoE influences AD and cerebral amyloid angiopathy (CAA) is via its effects on Ab metabolism (Kim et al. 2009a; Castellano et al. 2011).”