Supramolecular Copolymerization of Glycopeptide Amphiphiles and Amyloid Peptides Improves Neuron Survival

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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.
Funding Information
  • Ministerio de Ciencia, Innovaci?n y Universidades (RYC2019-026980-I, RYC2020-028732-I)
  • Ministerio de Ciencia y Tecnolog?a (CNS2022-135407, CNS2023-144820, PID2020-114407RA-I00, PID2021-124839OA-I00)
  • Intramural Research Program (P199)
  • National Institute on Aging (R01AG086270)
  • NextGenerationEU
  • European Social Fund Plus
  • Center for Regenerative Nanomedicine, Northwestern University

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