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

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Abstract

After repeated frustrations with amyloid beta (Aβ)-targeted clinical trials for Alzheimer’s disease (AD) in recent years, the therapeutic focus of AD has gradually shifted from Aβ 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 Aβ 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.

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Acknowledgments

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).

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Authors and Affiliations

  1. 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

    Lin Zhu, Lin-Lin Xu, Ru-Jiang Ma & Lin-Qi Shi

  2. 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

    Fan Huang

  3. China Department of Colorectal Surgery, Tianjin Union Medical Center, Nankai University School of Medicine, Nankai University, Tianjin, Tianjin, 300074, China

    Ming-Qing Zhang

  4. Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, 300121, China

    Hao-Ren Jing & Xi-Peng Zhang

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  1. Lin Zhu
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Zhu, L., Zhang, MQ., Jing, HR. et al. Bioinspired Self-assembly Nanochaperone Inhibits Tau-Derived PHF6 Peptide Aggregation in Alzheimer’s Disease. Chin J Polym Sci 40, 1062–1070 (2022). https://doi.org/10.1007/s10118-022-2799-9

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