Pharmacodynamics in Alzheimer’s disease Model Rats of a Bifunctional Peptide with the Potential to Accelerate the Degradation and Reduce the Toxicity of Amyloid β-Cu Fibrils

Publication date: Available online 27 October 2017
Source:Acta Biomaterialia
Author(s): Dan Wang, Qian Zhang, Xiaoyu Hu, Wei Wang, Xushan Zhu, Zhi Yuan
The accumulation of the extracellular β-amyloid (Aβ) aggregates with metal ions in conjunction with reactive oxygen species (ROS) is closely related to the pathogenesis of Alzheimer's disease (AD). Accounting on Cu ions chelating of our previously designed bifunctional peptide GGHRYYAAFFARR (GR) as well as Aβ-Cu fibrils (fAβ-Cu) dissociation potentials, we report herein an efficient route to synthetically minimize ROS toxicity and degrade fAβ-Cu. It is worth mentioning that GR combines the metal chelating agent GGH and β-sheet breaker RYYAAFFARR (RR). The in vitro results have showed that GR disassociates fAβ-Cu into smaller fragments (sAβ-Cu, 150 - 200 nm), easily assimilated by PC12 cell and subsequently degraded in the lysosomes; GR can also suppress the ROS generated by fAβ-Cu. The viability of PC12 cell treated with fAβ-Cu has increased, from 38% to about 70% after administration of GR, overwhelming the GGH chelator (46%) and single functional peptide RR (48%). The in vivo results indicated that GR has efficiently reduced Aβ deposition, ameliorated neurologic changes and rescued memory loss, thus, enhancing the cognitive and spatial memory in a AD rat model. This study confirms the superior effect of GR and paves the way toward its future employment in large scale AD treatment.SignificanceWe have focused on accelerating the degradation of fAβ-Cu as well as synthetically reducing the ROS toxicity by GR, and, consequently, its benefits in vivo. The bifunctional peptide GR can not only disaggregate fAβ-Cu into smaller fragments to facilitate uptake and degradation by PC12 cell, but also suppresses the ROS generated by fAβ-Cu. Thus, the viability of PC12 cell treated with fAβ-Cu has increased from 38% to 70% after GR administration, overwhelming GGH (46%) and RR (48%). The in vivo studies have revealed that GR improves the spatial memory ability and reduce the amount of senile plaques within brain of AD model rats. Thus, we suppose the bifunctional inhibitor GR has good application prospects in the treatment of AD treatment.

Graphical abstract

http://ift.tt/2gKjMP3