Abstract
Neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis are characterized by progressive neuronal loss and the accumulation of misfolded proteins including amyloid proteins. Current therapeutic options include the use of antibodies for these proteins, but novel chemical strategies need to be developed. The disaccharide trehalose has been widely reported to prevent misfolding and aggregation of proteins, and we therefore investigated the conjugation of this moiety to biocompatible peptide amphiphiles (TPAs) known to undergo supramolecular polymerization. Using X-ray scattering, circular dichroism, and infrared spectroscopy, we found that trehalose conjugation destabilized the internal β-sheet structures within the TPA supramolecular polymers as evidenced by a lower thermal transition. Thioflavin T fluorescence showed that these metastable TPA nanofibers suppressed A42 aggregation. Interestingly, we found that the suppression involved supramolecular copolymerization of TPA polymers with Aβ42, which effectively trapped the peptides within the filamentous structures. In vitro assays with human induced pluripotent stem cell-derived neurons demonstrated that these TPAs significantly improved neuron survival compared to other conditions. Our study highlights the potential of properly tuned supramolecular polymerizations of monomers to safely remove amyloidogenic proteins in neurodegeneration.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 17710-17724 |
| Number of pages | 15 |
| Journal | Journal of the American Chemical Society |
| Volume | 147 |
| Issue number | 21 |
| DOIs | |
| State | Published - May 28 2025 |
Funding
This work was primarily supported by the Center for Regenerative Nanomedicine. Additional support was provided by Grants PID2021-124839OA-I00 and CNS2022-135407 (Z.A.), and PID2020-114407RA-I00 and CNS2023-144820 (J.A.O.) funded by Spanish Ministry of Science MICIU/AEI/10.13039/501100011033 and European Union NextGenerationEU/PRTR. The authors thank Ramon y Cajal fellowship RYC2020-028732-I (Z.A.) and RYC2019-026980-I (J.A.O.), the FPI fellowship PRE2022-101803 (P.C.) funded by MICIU/AEI/10.13039/501100011033 and FSE+. Research reported in this publication was supported by the National Institute On Aging of the National Institutes of Health under Award Number R01AG086270 and the Contract/Research supported by IRP Research Grant (contract number P199). Research reported in this publication was also supported by the Chemistry of Life Processed Predoctoral Training Program at Northwestern University. We acknowledge use of the following core facilities at Northwestern University: the Peptide Synthesis Core Facility and the Analytical bioNanoTechnology Core Facility of the Center for Regenerative Nanomedicine, which has current support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633), Keck Biophysics Facility, a shared resource of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University supported in part by the NCI Cancer Center Support grant #P30 CA060553, the Keck-II facility and the BioCryo facility of Northwestern University\u2019s NUANCE Center, which has received support from the SHyNE Resource (NSF ECCS-2025633), and the IMSERC NMR and MS facility at Northwestern University, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633), NIH 1S10OD012016-01/1S10RR019071-01A1, Northwestern University, the IIN, and Northwestern\u2019s MRSEC program (NSF DMR-1720139). This research was supported in part through the computational resources and staff contributions provided for the Quest high performance computing facility at Northwestern University which is jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology. We also thank the IBEC Core Facility and Microscopy Characterization Facility, Unit 7 of ICTS \u201CNANBIOSIS\u201D from CIBER-BBN both at Institute for Bioengineering of Catalonia and Centro de Excelencia Severo Ochoa Grant CEX2023-001282-S, funded by MICIU/AEI/10.13039/501100011033. Elemental analysis was performed at the Northwestern University Quantitative Bioelement Imaging Center generously supported by the NIH under Grant S10OD020118. X-ray experiments were performed at the DuPont-Northwestern-Dow Collaborative Access Team (DND-CAT) located at Sector 5 of the Advanced Photon Source (APS). DND-CAT is supported by Northwestern University, The Dow Chemical Company, and DuPont de Nemours, Inc. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by the Argonne National Laboratory under contract no. DE-AC02-06CH11357. Data were collected using an instrument funded by the National Science Foundation under award number 0960140. We thank Mark Seniw for providing molecular graphics. The content is solely the responsibility of the authors and does not necessarily represent the official views of Northwestern University.
ASJC Scopus subject areas
- Catalysis
- General Chemistry
- Biochemistry
- Colloid and Surface Chemistry