Accumulation of ?-amyloid (A?) in the brain is essential to Alzheimer?s disease (AD) pathogenesis. Carriers of the apolipoprotein E (APOE) ?4 allele demonstrate greatly increased AD risk and enhanced brain A? deposition.
In contrast, APOE ?2 allele carries show reduced AD risk, later age of disease onset, and lesser A? accumulation. However, it remains elusive whether the apoE2 isoform exerts truly protective effect against A? pathology or apoE2 plays deleterious role albeit less pronounced than the apoE4 isoform.
Here, we characterized APPSW/PS1dE9/APOE ?2-TR (APP/E2) and APPSW/PS1dE9/APOE ?4-TR (APP/E4) mice, with targeted replacement (TR) of the murine Apoe for human ?2 or ?4 alleles, and used these models to investigate effects of pharmacological inhibition of the apoE/A? interaction on A? deposition and neuritic degeneration. APP/E2 and APP/E4 mice replicate differential effect of human apoE isoforms on A? pathology with APP/E4 mice showing a several-fold greater load of A? plaques, insoluble brain A? levels, A? 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 A?12-28P, a non-toxic, synthetic peptide homologous to the apoE binding motif within the A? sequence, which competitively blocks the apoE/A? interaction.
In both lines, the treatment significantly reduced brain A? accumulation, co-accumulation of apoE within A? plaques, and neuritic degeneration, and prevented memory deficit in APP/E4 mice. These results indicate that both apoE2 and apoE4 isoforms contribute to A? deposition and future therapies targeting the apoE/A? interaction could produce favorable outcome in APOE ?2 and ?4 allele carriers.
Author: Joanna E PankiewiczMaitea GuridiJungsu KimAyodeji A AsuniSandrine SanchezPatrick M SullivanDavid M HoltzmanMartin J. Sadowski
Credits/Source: Acta Neuropathologica Communications 2014, 2:75
Published on: 2014-06-29
Tweet
News Provider: 7thSpace Interactive / EUPB Press Office
Social Bookmarking
RETWEET This! | Digg this! | Post to del.icio.us | Post to Furl | Add to Netscape | Add to Yahoo! | Rojo
There are no comments available. Be the first to write a comment.