Bioinspired Self-assembly Nanochaperone Inhibits Tau-Derived PHF6 Peptide Aggregation in Alzheimer’s Disease

Lin Zhu; Ming-Qing Zhang; Hao-Ren Jing; Xi-Peng Zhang; Lin-Lin Xu; Ru-Jiang Ma; Fan Huang; Lin-Qi Shi

doi:10.1007/s10118-022-2799-9

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Bioinspired Self-assembly Nanochaperone Inhibits Tau-Derived PHF6 Peptide Aggregation in Alzheimer’s Disease

RESEARCH ARTICLE | Updated：2022-08-19

- Bioinspired Self-assembly Nanochaperone Inhibits Tau-Derived PHF6 Peptide Aggregation in Alzheimer’s Disease
- Bioinspired Self-assembly Nanochaperone Inhibits Tau-Derived PHF6 Peptide Aggregation in Alzheimer’s Disease
- 高分子科学（英文版） 2022年40卷第9期页码：1062-1070
- Affiliations：
  
  a.State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, Tianjin 300071, China
  b.Key Laboratory of Radiopharmacokinetics for Innovative Drugs, Chinese Academy of Medical Sciences, and Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, China
  c.Nankai University School of Medicine, Nankai University, Tianjin, China Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300074, China
  d.Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China
- Author bio：
  
  huangfan@irm-cams.ac.cn (F.H.)
  shilinqi@nankai.edu.cn (L.Q.S.)
- Funds：
  
  This work was financially supported by the National Natural Science Foundation of China (Nos. 51933006 and 52073306), Young Elite Scientists Sponsorship Program by Tianjin (No. TJSQNTJ-2020-18), the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2019-RC-HL-014) and Wenzhou Key Laboratory of Biomaterials and Engineering (No. WIUCASSWCL21004).
- DOI：10.1007/s10118-022-2799-9
  中图分类号：
- 纸质出版日期：2022-09-01，
  
  网络出版日期：2022-07-12，
  
  收稿日期：2022-03-30，
  
  修回日期：2022-05-07，
  
  录用日期：2022-05-09
- Accepted：
Scan QR Code
Zhu, L.; Zhang, M. Q.; Jing, H. R.; Zhang, X. P.; Xu, L. L.; Ma, R. J.; Huang, F.; Shi, L. Q. Bioinspired self-assembly nanochaperone inhibits tau-derived PHF6 peptide aggregation in Alzheimer’s disease. Chinese J. Polym. Sci. 2022, 40, 1062–1070

Lin Zhu, Ming-Qing Zhang, Hao-Ren Jing, et al. Bioinspired Self-assembly Nanochaperone Inhibits Tau-Derived PHF6 Peptide Aggregation in Alzheimer’s Disease[J]. Chinese Journal of Polymer Science, 2022,40(9):1062-1070.
Zhu, L.; Zhang, M. Q.; Jing, H. R.; Zhang, X. P.; Xu, L. L.; Ma, R. J.; Huang, F.; Shi, L. Q. Bioinspired self-assembly nanochaperone inhibits tau-derived PHF6 peptide aggregation in Alzheimer’s disease. Chinese J. Polym. Sci. 2022, 40, 1062–1070 DOI： 10.1007/s10118-022-2799-9.

Lin Zhu, Ming-Qing Zhang, Hao-Ren Jing, et al. Bioinspired Self-assembly Nanochaperone Inhibits Tau-Derived PHF6 Peptide Aggregation in Alzheimer’s Disease[J]. Chinese Journal of Polymer Science, 2022,40(9):1062-1070. DOI： 10.1007/s10118-022-2799-9.

摘要

Inspired by natural heat shock protein

we fabricated a self-assembly nanochaperone based on mixed-shell polymeric micelle (MSPM) as a novel tau-targeted AD therapy. With tunable phase-separated microdomains on surface

the nanochaperone could effectively bind with PHF6 aggregates

inhibit PHF6 aggregation

block neuronal internalization

thus significantly alleviating PHF6 mediated neurotoxicity.

Abstract

After repeated frustrations with amyloid beta (A

)-targeted clinical trials for Alzheimer’s disease (AD) in recent years

the therapeutic focus of AD has gradually shifted from A

to tau protein. The misfolding and aggregation of tau protein into neurofibrillary tangles (NFTs) cause neuron death and synaptic dysfunction

and the deposition of NFTs is more closely related to the severity of AD than A

plaques. Thus

it has great potential to target tau protein aggregation for AD treatment. The hexapeptide VQIVYK (known as PHF6) in tau protein has been found to play a dominant role for tau aggregation and was widely used as a model to design tau protein aggregation inhibitors. Here

inspired by natural heat shock protein (HSPs)

we fabricated a self-assembly nanochaperone based on mixed-shell polymeric micelle (MSPM) as a novel tau-targeted AD therapy. With tunable phase-separated microdomains on the surface

the nanochaperone could effectively bind with PHF6 aggregates

inhibit PHF6 aggregation

block neuronal internalization of PHF6 species

thus significantly alleviating PHF6 mediated neurotoxicity. Moreover

the as-prepared nanochaperone could work with proteinase to facilitate the degradation of PHF6 aggregates. This bioinspired nanochaperone demonstrated a new way to target tau protein and provided a promising strategy for AD treatment.

关键词

Keywords

Alzheimer’s diseaseTau proteinPHF6NanochaperoneInhibition

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Catalysis and Inhibition of Benzimidazole Units on Thermal Imidization of Poly(amic acid) via Hydrogen Bonding Interactions