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Heptameric Peptide Interferes with Amyloid-β Aggregation by Structural Reorganization of the Toxic Oligomers

[Image: see text] Pathogenesis of Alzheimer’s disease (AD), the most common type of dementia, involves misfolding and aggregation of the extracellular amyloid-β (Aβ) protein where the intermediate oligomers, formed during the aggregation progression cascade, are considered the prime toxic species. H...

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Autores principales: Bhattacharyya, Rajanya, Bhattacharjee, Sayan, Pathak, Bani K., Sengupta, Jayati
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346273/
https://www.ncbi.nlm.nih.gov/pubmed/32656435
http://dx.doi.org/10.1021/acsomega.0c01730
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author Bhattacharyya, Rajanya
Bhattacharjee, Sayan
Pathak, Bani K.
Sengupta, Jayati
author_facet Bhattacharyya, Rajanya
Bhattacharjee, Sayan
Pathak, Bani K.
Sengupta, Jayati
author_sort Bhattacharyya, Rajanya
collection PubMed
description [Image: see text] Pathogenesis of Alzheimer’s disease (AD), the most common type of dementia, involves misfolding and aggregation of the extracellular amyloid-β (Aβ) protein where the intermediate oligomers, formed during the aggregation progression cascade, are considered the prime toxic species. Here, we identify an active peptide fragment from a medicinal plant-derived (Aristolochia indica) fibrinolytic enzyme having anti-amyloidogenic effects against Aβ fibrillation and toxicity. Liquid chromatography with tandem mass spectrometry (LC-MS/MS), followed by computational analysis of the peptide pool generated by proteolytic digestion of the enzyme, identifies two peptide sequences with predictive high-propensity binding to Aβ(42). Microscopic visualizations in conjunction with biochemical and biophysical assessments suggest that the synthetic version of one of the peptides (termed here P(active), GFLLHQK) arrests Aβ molecules in off-pathway oligomers that can no longer participate in the cytotoxic fibrillation pathway. In contrast, the other peptide (termed P(1)) aggravates the fibrillation process. Further investigations confirm the strong binding affinity of P(active) with both Aβ(42) monomers and toxic oligomers by biolayer interferometric assays. We have also shown that, mechanistically, P(active) binding induces conformational alterations in the Aβ molecule along with modification of Aβ hydrophobicity, one of the key players in aggregation. Importantly, the biostability of P(active) in human blood serum and its nontoxic nature make it a promising therapeutic candidate against Alzheimer’s, for which no disease-modifying treatments are available to date.
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spelling pubmed-73462732020-07-10 Heptameric Peptide Interferes with Amyloid-β Aggregation by Structural Reorganization of the Toxic Oligomers Bhattacharyya, Rajanya Bhattacharjee, Sayan Pathak, Bani K. Sengupta, Jayati ACS Omega [Image: see text] Pathogenesis of Alzheimer’s disease (AD), the most common type of dementia, involves misfolding and aggregation of the extracellular amyloid-β (Aβ) protein where the intermediate oligomers, formed during the aggregation progression cascade, are considered the prime toxic species. Here, we identify an active peptide fragment from a medicinal plant-derived (Aristolochia indica) fibrinolytic enzyme having anti-amyloidogenic effects against Aβ fibrillation and toxicity. Liquid chromatography with tandem mass spectrometry (LC-MS/MS), followed by computational analysis of the peptide pool generated by proteolytic digestion of the enzyme, identifies two peptide sequences with predictive high-propensity binding to Aβ(42). Microscopic visualizations in conjunction with biochemical and biophysical assessments suggest that the synthetic version of one of the peptides (termed here P(active), GFLLHQK) arrests Aβ molecules in off-pathway oligomers that can no longer participate in the cytotoxic fibrillation pathway. In contrast, the other peptide (termed P(1)) aggravates the fibrillation process. Further investigations confirm the strong binding affinity of P(active) with both Aβ(42) monomers and toxic oligomers by biolayer interferometric assays. We have also shown that, mechanistically, P(active) binding induces conformational alterations in the Aβ molecule along with modification of Aβ hydrophobicity, one of the key players in aggregation. Importantly, the biostability of P(active) in human blood serum and its nontoxic nature make it a promising therapeutic candidate against Alzheimer’s, for which no disease-modifying treatments are available to date. American Chemical Society 2020-06-25 /pmc/articles/PMC7346273/ /pubmed/32656435 http://dx.doi.org/10.1021/acsomega.0c01730 Text en Copyright © 2020 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Bhattacharyya, Rajanya
Bhattacharjee, Sayan
Pathak, Bani K.
Sengupta, Jayati
Heptameric Peptide Interferes with Amyloid-β Aggregation by Structural Reorganization of the Toxic Oligomers
title Heptameric Peptide Interferes with Amyloid-β Aggregation by Structural Reorganization of the Toxic Oligomers
title_full Heptameric Peptide Interferes with Amyloid-β Aggregation by Structural Reorganization of the Toxic Oligomers
title_fullStr Heptameric Peptide Interferes with Amyloid-β Aggregation by Structural Reorganization of the Toxic Oligomers
title_full_unstemmed Heptameric Peptide Interferes with Amyloid-β Aggregation by Structural Reorganization of the Toxic Oligomers
title_short Heptameric Peptide Interferes with Amyloid-β Aggregation by Structural Reorganization of the Toxic Oligomers
title_sort heptameric peptide interferes with amyloid-β aggregation by structural reorganization of the toxic oligomers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346273/
https://www.ncbi.nlm.nih.gov/pubmed/32656435
http://dx.doi.org/10.1021/acsomega.0c01730
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