Rationally designed dehydroalanine (ΔAla)-containing peptides inhibit amyloid-β (Aβ) peptide aggregation

Vijayaraghavan Rangachari, Zachary S. Davey, Brent Healy, Brenda D. Moore, Leilani K. Sonoda, Bernadette Cusack, Ghulam M. Maharvi, Abdul H. Fauq, Terrone L. Rosenberry

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Among the pathological hallmarks of Alzheimer's disease (AD) is the deposition of amyloid-b (Aβ) peptides, primarily Aβ (1-40) and Aβ (1-42), in the brain as senile plaques. A large body of evidence suggests that cognitive decline and dementia in AD patients arise from the formation of various aggregated forms of Aβ, including oligomers, protofibrils and fibrils. Hence, there is increasing interest in designing molecular agents that can impede the aggregation process and that can lead to the development of therapeutically viable compounds. Here, we demonstrate the ability of the specifically designed α,β-dehydroalanine (ΔAla)-containing peptides P1 (K-L-V-F-ΔA-I-ΔA) and P2 (K-F-ΔA-ΔA-ΔA-F) to inhibit Aβ (1-42) aggregation. The mechanism of interaction of the two peptides with Aβ (1-42) seemed to be different and distinct. Overall, the data reveal a novel application of ΔAla-containing peptides as tools to disrupt Aβ aggregation that may lead to the development of anti-amyloid therapies not only for AD but also for many other protein misfolding diseases.

Original languageEnglish (US)
Pages (from-to)456-465
Number of pages10
JournalBiopolymers
Volume91
Issue number6
DOIs
StatePublished - 2009

Fingerprint

Amyloid
Peptides
Agglomeration
Alzheimer Disease
Proteostasis Deficiencies
Aptitude
Amyloid Plaques
Oligomers
Dementia
Brain
Proteins
dehydroalanine
Therapeutics

Keywords

  • Amyloid aggregation
  • Dehydro-alanine
  • Inhibition
  • Rational design

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Organic Chemistry
  • Biomaterials

Cite this

Rangachari, V., Davey, Z. S., Healy, B., Moore, B. D., Sonoda, L. K., Cusack, B., ... Rosenberry, T. L. (2009). Rationally designed dehydroalanine (ΔAla)-containing peptides inhibit amyloid-β (Aβ) peptide aggregation. Biopolymers, 91(6), 456-465. https://doi.org/10.1002/bip.21151

Rationally designed dehydroalanine (ΔAla)-containing peptides inhibit amyloid-β (Aβ) peptide aggregation. / Rangachari, Vijayaraghavan; Davey, Zachary S.; Healy, Brent; Moore, Brenda D.; Sonoda, Leilani K.; Cusack, Bernadette; Maharvi, Ghulam M.; Fauq, Abdul H.; Rosenberry, Terrone L.

In: Biopolymers, Vol. 91, No. 6, 2009, p. 456-465.

Research output: Contribution to journalArticle

Rangachari, V, Davey, ZS, Healy, B, Moore, BD, Sonoda, LK, Cusack, B, Maharvi, GM, Fauq, AH & Rosenberry, TL 2009, 'Rationally designed dehydroalanine (ΔAla)-containing peptides inhibit amyloid-β (Aβ) peptide aggregation', Biopolymers, vol. 91, no. 6, pp. 456-465. https://doi.org/10.1002/bip.21151
Rangachari, Vijayaraghavan ; Davey, Zachary S. ; Healy, Brent ; Moore, Brenda D. ; Sonoda, Leilani K. ; Cusack, Bernadette ; Maharvi, Ghulam M. ; Fauq, Abdul H. ; Rosenberry, Terrone L. / Rationally designed dehydroalanine (ΔAla)-containing peptides inhibit amyloid-β (Aβ) peptide aggregation. In: Biopolymers. 2009 ; Vol. 91, No. 6. pp. 456-465.
@article{f9f87e357fb04f6894417388f09dcfb0,
title = "Rationally designed dehydroalanine (ΔAla)-containing peptides inhibit amyloid-β (Aβ) peptide aggregation",
abstract = "Among the pathological hallmarks of Alzheimer's disease (AD) is the deposition of amyloid-b (Aβ) peptides, primarily Aβ (1-40) and Aβ (1-42), in the brain as senile plaques. A large body of evidence suggests that cognitive decline and dementia in AD patients arise from the formation of various aggregated forms of Aβ, including oligomers, protofibrils and fibrils. Hence, there is increasing interest in designing molecular agents that can impede the aggregation process and that can lead to the development of therapeutically viable compounds. Here, we demonstrate the ability of the specifically designed α,β-dehydroalanine (ΔAla)-containing peptides P1 (K-L-V-F-ΔA-I-ΔA) and P2 (K-F-ΔA-ΔA-ΔA-F) to inhibit Aβ (1-42) aggregation. The mechanism of interaction of the two peptides with Aβ (1-42) seemed to be different and distinct. Overall, the data reveal a novel application of ΔAla-containing peptides as tools to disrupt Aβ aggregation that may lead to the development of anti-amyloid therapies not only for AD but also for many other protein misfolding diseases.",
keywords = "Amyloid aggregation, Dehydro-alanine, Inhibition, Rational design",
author = "Vijayaraghavan Rangachari and Davey, {Zachary S.} and Brent Healy and Moore, {Brenda D.} and Sonoda, {Leilani K.} and Bernadette Cusack and Maharvi, {Ghulam M.} and Fauq, {Abdul H.} and Rosenberry, {Terrone L.}",
year = "2009",
doi = "10.1002/bip.21151",
language = "English (US)",
volume = "91",
pages = "456--465",
journal = "Biopolymers",
issn = "0006-3525",
publisher = "John Wiley and Sons Inc.",
number = "6",

}

TY - JOUR

T1 - Rationally designed dehydroalanine (ΔAla)-containing peptides inhibit amyloid-β (Aβ) peptide aggregation

AU - Rangachari, Vijayaraghavan

AU - Davey, Zachary S.

AU - Healy, Brent

AU - Moore, Brenda D.

AU - Sonoda, Leilani K.

AU - Cusack, Bernadette

AU - Maharvi, Ghulam M.

AU - Fauq, Abdul H.

AU - Rosenberry, Terrone L.

PY - 2009

Y1 - 2009

N2 - Among the pathological hallmarks of Alzheimer's disease (AD) is the deposition of amyloid-b (Aβ) peptides, primarily Aβ (1-40) and Aβ (1-42), in the brain as senile plaques. A large body of evidence suggests that cognitive decline and dementia in AD patients arise from the formation of various aggregated forms of Aβ, including oligomers, protofibrils and fibrils. Hence, there is increasing interest in designing molecular agents that can impede the aggregation process and that can lead to the development of therapeutically viable compounds. Here, we demonstrate the ability of the specifically designed α,β-dehydroalanine (ΔAla)-containing peptides P1 (K-L-V-F-ΔA-I-ΔA) and P2 (K-F-ΔA-ΔA-ΔA-F) to inhibit Aβ (1-42) aggregation. The mechanism of interaction of the two peptides with Aβ (1-42) seemed to be different and distinct. Overall, the data reveal a novel application of ΔAla-containing peptides as tools to disrupt Aβ aggregation that may lead to the development of anti-amyloid therapies not only for AD but also for many other protein misfolding diseases.

AB - Among the pathological hallmarks of Alzheimer's disease (AD) is the deposition of amyloid-b (Aβ) peptides, primarily Aβ (1-40) and Aβ (1-42), in the brain as senile plaques. A large body of evidence suggests that cognitive decline and dementia in AD patients arise from the formation of various aggregated forms of Aβ, including oligomers, protofibrils and fibrils. Hence, there is increasing interest in designing molecular agents that can impede the aggregation process and that can lead to the development of therapeutically viable compounds. Here, we demonstrate the ability of the specifically designed α,β-dehydroalanine (ΔAla)-containing peptides P1 (K-L-V-F-ΔA-I-ΔA) and P2 (K-F-ΔA-ΔA-ΔA-F) to inhibit Aβ (1-42) aggregation. The mechanism of interaction of the two peptides with Aβ (1-42) seemed to be different and distinct. Overall, the data reveal a novel application of ΔAla-containing peptides as tools to disrupt Aβ aggregation that may lead to the development of anti-amyloid therapies not only for AD but also for many other protein misfolding diseases.

KW - Amyloid aggregation

KW - Dehydro-alanine

KW - Inhibition

KW - Rational design

UR - http://www.scopus.com/inward/record.url?scp=67650604644&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67650604644&partnerID=8YFLogxK

U2 - 10.1002/bip.21151

DO - 10.1002/bip.21151

M3 - Article

C2 - 19189374

AN - SCOPUS:67650604644

VL - 91

SP - 456

EP - 465

JO - Biopolymers

JF - Biopolymers

SN - 0006-3525

IS - 6

ER -