Effects of Single Amino Acid Substitutions on Aggregation and Cytotoxicity Properties of Amyloid β Peptide

Ana Esther Estrada-Rodríguez, Donato Valdez-Pérez, Jaime Ruiz-García, Alejandro Treviño-Garza, Ana Miriam Gómez-Martínez, Herminia Guadalupe Martínez-Rodríguez, Ana María Rivas-Estilla, Román Vidaltamayo, Viviana Zomosa-Signoret

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Abstract

© 2018 Springer Science+Business Media, LLC, part of Springer Nature Alzheimer’s disease is the main cause of dementia and the deposition of amyloid beta peptide (Aβ) in the brain is the key event in its progression. Soluble oligomers of Aβ are proposed to be the primary neurotoxic agents, and prevention of Aβ self-assembly has been proposed as a therapeutic approach. To analyze the role of key amino acids for Aβ aggregation and cytotoxicity, we introduced the three single mutations K28A, A30W or M35C in three length variants of Aβ: 25–35, 1–40, 1–42, 1–40. We assessed amyloid formation through atomic force microscopy and thioflavine fluorescence and tested the amyloid seeding effects of the mutant peptides in co-incubation assays. We also correlated changes in aggregation properties with cytotoxicity and reactive oxygen species production. Atomic force microscopy imaging demonstrated that the formation of amyloid fibrils was more dependent on the primary sequence of the peptides rather than on their length. We observe decreased formation of amyloid-like structures in all the three mutant Aβ (25–35) peptides, but these short peptide mutants remained cytotoxic. A30W and M35C mutants of the longer peptides decreased reactive oxygen species production and this effect was correlated with lower levels of cytotoxicity, but not with aggregation properties. Taken together, our results show that cytotoxicity of the Aβ peptide variants is more dependent on their primary amino acid sequence than on their capability to aggregate into amyloid-like structures.
Original languageEnglish
Pages (from-to)493-509
Number of pages17
JournalInternational Journal of Peptide Research and Therapeutics
Volume25
Issue number2
Early online date14 Mar 2018
DOIs
Publication statusPublished - 1 Jun 2019

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All Science Journal Classification (ASJC) codes

  • Analytical Chemistry
  • Bioengineering
  • Biochemistry
  • Molecular Medicine
  • Drug Discovery

Cite this

Estrada-Rodríguez, A. E., Valdez-Pérez, D., Ruiz-García, J., Treviño-Garza, A., Gómez-Martínez, A. M., Martínez-Rodríguez, H. G., Rivas-Estilla, A. M., Vidaltamayo, R., & Zomosa-Signoret, V. (2019). Effects of Single Amino Acid Substitutions on Aggregation and Cytotoxicity Properties of Amyloid β Peptide. International Journal of Peptide Research and Therapeutics, 25(2), 493-509. https://doi.org/10.1007/s10989-018-9693-x