{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:58:37Z","timestamp":1787029117773,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T00:00:00Z","timestamp":1729728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22178259"],"award-info":[{"award-number":["22178259"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The deposition of amyloid \u03b2-protein (A\u03b2) in the brain is the main pathogenesis of Alzheimer\u2019s disease (AD). The development of potent inhibitors against A\u03b2 aggregation is one of the effective strategies to combat AD. Endogenous transthyretin (TTR) can inhibit A\u03b2 fibrillization via hydrophobic interactions, but its weak inhibitory potency hinders its application in AD therapy. Here, different recombinant TTRs were designed by cationic surface charge engineering. Compared with TTR, all positively charged recombinant TTRs showed enhanced capability in inhibiting A\u03b2 aggregation, especially the recombinant protein obtained by mutating the acidic amino acid in TTR to arginine (TTR-nR) exhibited excellent inhibitory effect. Among them, TTR-7R remarkably increased the inhibitory potency against A\u03b2, which could effectively inhibit A\u03b240 fibrillization at a very low concentration (0.5 \u03bcM). In addition, TTR-7R increased cultured cell viability from 62% to 89%, scavenged amyloid plaques in AD nematodes, and prolonged nematode lifespan by 5 d at 2 \u03bcM. Thermodynamic studies demonstrated that TTR-7R, enriching in positive charges, presented hydrophobic interactions and enhanced electrostatic interactions with A\u03b240, leading to a significantly enhanced inhibitory capacity of TTR-7R. The research provided insights into the development of efficient recombinant protein inhibitors for AD treatment.<\/jats:p>","DOI":"10.3390\/molecules29215023","type":"journal-article","created":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T09:11:47Z","timestamp":1729761107000},"page":"5023","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cationic Surface Charge Engineering of Recombinant Transthyretin Remarkably Increases the Inhibitory Potency Against Amyloid \u03b2-Protein Fibrillogenesis"],"prefix":"10.3390","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8712-174X","authenticated-orcid":false,"given":"Xiaoding","family":"Lin","sequence":"first","affiliation":[{"name":"Key Laboratory of Systems Bioengineering and Frontiers Science Center for Synthetic Biology (Ministry of Education), Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5271-9696","authenticated-orcid":false,"given":"Ting","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Bioengineering and Frontiers Science Center for Synthetic Biology (Ministry of Education), Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqi","family":"Hou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Bioengineering and Frontiers Science Center for Synthetic Biology (Ministry of Education), Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Dong","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Bioengineering and Frontiers Science Center for Synthetic Biology (Ministry of Education), Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5256-9571","authenticated-orcid":false,"given":"Yan","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Systems Bioengineering and Frontiers Science Center for Synthetic Biology (Ministry of Education), Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1136\/bmj.322.7300.1447","article-title":"Midlife vascular risk factors and Alzheimer\u2019s disease in later life: Longitudinal, population based study","volume":"322","author":"Kivipelto","year":"2001","journal-title":"BMJ"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"23780","DOI":"10.1039\/C8RA03620A","article-title":"Current progress, challenges and future prospects of diagnostic and therapeutic interventions in Alzheimer\u2019s disease","volume":"8","author":"Rajasekhar","year":"2018","journal-title":"RSC Adv."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/nrneurol.2017.162","article-title":"Amyloid-\u03b2 and tau complexity\u2014Towards improved biomarkers and targeted therapies","volume":"14","author":"Polanco","year":"2018","journal-title":"Nat. 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