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

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
Article number10.1007/s10989-018-9693-x
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

Bibliographical note

Funding Information:
Funding This work was supported by the Consejo Nacional de Cien-cia y Tecnología (CONACYT) of Mexico [grant numbers: CB-2014-22006 to V.C.Zomosa-Signoret, CB-2013-220342 to R. Vidaltamayo and FC-2015-341 to J. Ruiz-García]. Ana Estrada was a recipient of a Doctoral fellowship from CONACYT.

Publisher Copyright:
© 2018, Springer Science+Business Media, LLC, part of Springer Nature.

All Science Journal Classification (ASJC) codes

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

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