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.
|Number of pages||17|
|Journal||International Journal of Peptide Research and Therapeutics|
|Early online date||14 Mar 2018|
|Publication status||Published - 1 Jun 2019|
Bibliographical noteFunding 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.
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All Science Journal Classification (ASJC) codes
- Analytical Chemistry
- Molecular Medicine
- Drug Discovery