| First Author | Pankiewicz JE | Year | 2014 |
| Journal | Acta Neuropathol Commun | Volume | 2 |
| Pages | 75 | PubMed ID | 24972680 |
| Mgi Jnum | J:357882 | Mgi Id | MGI:7539657 |
| Doi | 10.1186/s40478-014-0075-0 | Citation | Pankiewicz JE, et al. (2014) Blocking the apoE/Abeta interaction ameliorates Abeta-related pathology in APOE epsilon2 and epsilon4 targeted replacement Alzheimer model mice. Acta Neuropathol Commun 2:75 |
| abstractText | Accumulation of beta-amyloid (Abeta) in the brain is essential to Alzheimer's disease (AD) pathogenesis. Carriers of the apolipoprotein E (APOE) epsilon4 allele demonstrate greatly increased AD risk and enhanced brain Abeta deposition. In contrast, APOE epsilon2 allele carries show reduced AD risk, later age of disease onset, and lesser Abeta accumulation. However, it remains elusive whether the apoE2 isoform exerts truly protective effect against Abeta pathology or apoE2 plays deleterious role albeit less pronounced than the apoE4 isoform. Here, we characterized APPSW/PS1dE9/APOE epsilon2-TR (APP/E2) and APPSW/PS1dE9/APOE epsilon4-TR (APP/E4) mice, with targeted replacement (TR) of the murine Apoe for human epsilon2 or epsilon4 alleles, and used these models to investigate effects of pharmacological inhibition of the apoE/Abeta interaction on Abeta deposition and neuritic degeneration. APP/E2 and APP/E4 mice replicate differential effect of human apoE isoforms on Abeta pathology with APP/E4 mice showing a several-fold greater load of Abeta plaques, insoluble brain Abeta levels, Abeta oligomers, and density of neuritic plaques than APP/E2 mice. Furthermore, APP/E4 mice, but not APP/E2 mice, exhibit memory impairment on object recognition and radial arm maze tests. Between the age of 6 and 10 months APP/E2 and APP/E4 mice received treatment with Abeta12-28P, a non-toxic, synthetic peptide homologous to the apoE binding motif within the Abeta sequence, which competitively blocks the apoE/Abeta interaction. In both lines, the treatment significantly reduced brain Abeta accumulation, co-accumulation of apoE within Abeta plaques, and neuritic degeneration, and prevented memory deficit in APP/E4 mice. These results indicate that both apoE2 and apoE4 isoforms contribute to Abeta deposition and future therapies targeting the apoE/Abeta interaction could produce favorable outcome in APOE epsilon2 and epsilon4 allele carriers. |
