Citation: Qian Zhang, Zhi Yuan. Study of Aβ Aggregation Inhibitors Based on Multiple Weak Interactions[J]. Acta Polymerica Sinica, ;2018, 0(7): 776-785. doi: 10.11777/j.issn1000-3304.2018.18025 shu

Study of Aβ Aggregation Inhibitors Based on Multiple Weak Interactions

Qian Zhang ¹ ,
Zhi Yuan ^1,2,,

1.
Key Laboratory of Functional Polymer Materials of the Ministry of Education, College of Chemistry, Tianjin 300071
2.
Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071

Corresponding author: Zhi Yuan, zhiy@nankai.edu.cn
Received Date: 21 January 2018
Revised Date: 17 April 2018

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with the loss of memory, cognitive decline, and behavioral disability, leading to dementia and death ultimately. The pathogenesis of AD is still unclear, but it is generally accepted that the occurrence of AD is related to the accumulation of amyloid β (Aβ) in the brain and the oxidative stress effect caused by the enrichment of metal ions. In our previous work, we expanded the targeting site from Aβ16-22 to Aβ11-23 (EVHHQKLVFFAED), which could offer multiple weak interaction sites, such as the electrostatic, hydrophobic interactions and hydrogen bonding. We designed and screened a novel Aβ aggregation inhibitory peptide (RR) by computer simulation. The tripeptide chelator GGH, selected by ITC experiment with selectively Cu ion chelating ability, was introduced into RR to get the bifunctional peptide inhibitor GR, which have the ability to inhibit Aβ aggregation and produce the oxygen species (ROS) production at the same time. The results of ThT fluorescence, turbidity analysis, MTT methods showed that GR can inhibit the aggregation of Aβ and Aβ-Cu complex (Aβ:Cu = 1:0.25) to form amorphous aggregates, and the cell survival of GR group can reach 88%, significantly higher than chelator GGH (49%) and single functional inhibitor RR (68%). Moreover, it is proposed for the first time that the endocytosis of Aβ aggregates in the brain could be promoted by the disaggregation of Aβ or Aβ-Cu complex fibrils to achieve the effect of treating AD. The results showed that RR and GR can disaggregate Aβ and Aβ-Cu complex fibrils to nanorod-like structure with a length of 200 − 250 nm (rA β), and β-sheet structure content in the system was reduced by 45%. rAβ more easily to PC12 cell endocytosis, and it can enter the cells and further into the cell lysosomes. The in vitro lysosomal cathepsin B (CatB) degradation experimental results showed that, compared to fAβ, rAβ is more susceptible to CatB degradation, and its degradation products have no longer full hydrophobic core region, thereby greatly reducing their chances of re-aggregation. Finally the feasibility of GR and RR has been verified in Morris water maze test.
- Alzheimer’s disease,
- Amyloid β,
- Peptide inhibitor
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