ApoE mimetic peptide decreases Aβ production in vitro and in vivo

Background: Apolipoprotein E (apoE) is postulated to affect brain A beta levels through multiple mechanisms-by altering amyloid precursor protein (APP) processing, A beta degradation, and A beta clearance. We previously showed that an apoE-derived peptide containing a double repeat of the receptor-binding region was similarly effective in increasing APP processing in vivo. Here, we further examined whether peptides containing tandem repeats of the apoE receptor-binding region (amino acids 141-149) affected APP trafficking, APP processing, and A beta production. Results: We found that peptides containing a double or triple tandem repeat of the apoE receptor-binding region, LRKLRKRLL, increased cell surface APP and decreased A beta levels in PS1-overexpressing PS70 cells and in primary neurons. This effect was potentiated by a sequential increase in the number of apoE receptor-binding domain repeats (trimer > dimer > monomer). We previously showed that the apoE dimer increased APP CTF in vivo; to determine whether the dimer also affected secreted APP or A beta levels, we performed a single hippocampal injection of the apoE dimer in wild-type mice and analyzed its effect on APP processing. We found increased sAPP alpha and decreased A beta levels at 24 hrs after treatment, suggesting that the apoE dimer may increase alpha-secretase cleavage. Conclusions: These data suggest that small peptides consisting of tandem repeats of the apoE receptor-binding region are sufficient to alter APP trafficking and processing. The potency of these peptides increased with increasing repeats of the receptor binding domain of apoE. In addition, in vivo administration of the apoE peptide (dimer) increased sAPP alpha and decreased A beta levels in wild-type mice. Overall, these findings contribute to our understanding of the effects of apoE on APP processing and A beta production both in vitro and in vivo.