The influence of the central region containing residues 19-25 on the aggregation properties and secondary structure of Alzheimer's β-amyloid peptide

Omar Ali El-Agnaf, David J S Guthrie, Dominic M. Walsh, G. Brent Irvine

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Alzheimer's β-amyloid peptide (Aβ) is a 39- to 43-amino-acid peptide that is the major component of neuritic plaques found in Alzheimer's disease (AD). The central region of Aβ plays a crucial role in many of its properties, including aggregation, neurotoxicity, proteolytic processing and interactions with other proteins, such as apolipoprotein E. Two mutations in this region, Ala21→Gly and Glu22→Gln, give rise to early onset forms of disease. We have studied several peptides based on the central region of Aβ in order to clarify the influence of specific amino acid residues on physicochemical behaviour. To avoid difficulties due to oxidation of Met35, the latter was replaced by the amino acid isostere, norleucine (Ahx), giving [Ahx35]Aβ-(25-35)-amide as a prototype structure. To this prototype, addition of pairs of amino acid residues from the sequence of Aβ, forming the corresponding 23-, 21- and 19-35 derivatives, resulted in peptides that aggregated to form fibrils of diameter 6-10 nm. The rate of aggregation was more rapid as peptide length increased. Circular dichroism spectra of aged solutions of peptides revealed that aggregation was accompanied by a transition from random structure to β sheet for some, but not all, peptides. The mutation from Ala to Gly at position 21 increased the rate of aggregation and altered the tendency to adopt secondary structure in the direction away from α helix and towards β sheet. In individuals with the Ala21→Gly mutation, these results would suggest that truncated species with N-termini in the region containing residues 17-20 would be more amyloidogenic than the wild type homologues.

Original languageEnglish
Pages (from-to)560-569
Number of pages10
JournalEuropean Journal of Biochemistry
Volume256
Issue number3
DOIs
Publication statusPublished - 15 Sep 1998
Externally publishedYes

Fingerprint

Amyloid
Agglomeration
Peptides
Amino Acids
Mutation
Norleucine
Amyloid Plaques
Apolipoproteins E
Circular Dichroism
Amides
Amino Acid Sequence
Alzheimer Disease
Derivatives
Oxidation
Processing
Proteins

Keywords

  • Aβ aggregation
  • Alzheimer's disease
  • Amyloid
  • Secondary structure

ASJC Scopus subject areas

  • Biochemistry

Cite this

The influence of the central region containing residues 19-25 on the aggregation properties and secondary structure of Alzheimer's β-amyloid peptide. / Ali El-Agnaf, Omar; Guthrie, David J S; Walsh, Dominic M.; Irvine, G. Brent.

In: European Journal of Biochemistry, Vol. 256, No. 3, 15.09.1998, p. 560-569.

Research output: Contribution to journalArticle

@article{49240b29d8484d31be3628e27808760f,
title = "The influence of the central region containing residues 19-25 on the aggregation properties and secondary structure of Alzheimer's β-amyloid peptide",
abstract = "Alzheimer's β-amyloid peptide (Aβ) is a 39- to 43-amino-acid peptide that is the major component of neuritic plaques found in Alzheimer's disease (AD). The central region of Aβ plays a crucial role in many of its properties, including aggregation, neurotoxicity, proteolytic processing and interactions with other proteins, such as apolipoprotein E. Two mutations in this region, Ala21→Gly and Glu22→Gln, give rise to early onset forms of disease. We have studied several peptides based on the central region of Aβ in order to clarify the influence of specific amino acid residues on physicochemical behaviour. To avoid difficulties due to oxidation of Met35, the latter was replaced by the amino acid isostere, norleucine (Ahx), giving [Ahx35]Aβ-(25-35)-amide as a prototype structure. To this prototype, addition of pairs of amino acid residues from the sequence of Aβ, forming the corresponding 23-, 21- and 19-35 derivatives, resulted in peptides that aggregated to form fibrils of diameter 6-10 nm. The rate of aggregation was more rapid as peptide length increased. Circular dichroism spectra of aged solutions of peptides revealed that aggregation was accompanied by a transition from random structure to β sheet for some, but not all, peptides. The mutation from Ala to Gly at position 21 increased the rate of aggregation and altered the tendency to adopt secondary structure in the direction away from α helix and towards β sheet. In individuals with the Ala21→Gly mutation, these results would suggest that truncated species with N-termini in the region containing residues 17-20 would be more amyloidogenic than the wild type homologues.",
keywords = "Aβ aggregation, Alzheimer's disease, Amyloid, Secondary structure",
author = "{Ali El-Agnaf}, Omar and Guthrie, {David J S} and Walsh, {Dominic M.} and Irvine, {G. Brent}",
year = "1998",
month = "9",
day = "15",
doi = "10.1046/j.1432-1327.1998.2560560.x",
language = "English",
volume = "256",
pages = "560--569",
journal = "FEBS Journal",
issn = "1742-464X",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - The influence of the central region containing residues 19-25 on the aggregation properties and secondary structure of Alzheimer's β-amyloid peptide

AU - Ali El-Agnaf, Omar

AU - Guthrie, David J S

AU - Walsh, Dominic M.

AU - Irvine, G. Brent

PY - 1998/9/15

Y1 - 1998/9/15

N2 - Alzheimer's β-amyloid peptide (Aβ) is a 39- to 43-amino-acid peptide that is the major component of neuritic plaques found in Alzheimer's disease (AD). The central region of Aβ plays a crucial role in many of its properties, including aggregation, neurotoxicity, proteolytic processing and interactions with other proteins, such as apolipoprotein E. Two mutations in this region, Ala21→Gly and Glu22→Gln, give rise to early onset forms of disease. We have studied several peptides based on the central region of Aβ in order to clarify the influence of specific amino acid residues on physicochemical behaviour. To avoid difficulties due to oxidation of Met35, the latter was replaced by the amino acid isostere, norleucine (Ahx), giving [Ahx35]Aβ-(25-35)-amide as a prototype structure. To this prototype, addition of pairs of amino acid residues from the sequence of Aβ, forming the corresponding 23-, 21- and 19-35 derivatives, resulted in peptides that aggregated to form fibrils of diameter 6-10 nm. The rate of aggregation was more rapid as peptide length increased. Circular dichroism spectra of aged solutions of peptides revealed that aggregation was accompanied by a transition from random structure to β sheet for some, but not all, peptides. The mutation from Ala to Gly at position 21 increased the rate of aggregation and altered the tendency to adopt secondary structure in the direction away from α helix and towards β sheet. In individuals with the Ala21→Gly mutation, these results would suggest that truncated species with N-termini in the region containing residues 17-20 would be more amyloidogenic than the wild type homologues.

AB - Alzheimer's β-amyloid peptide (Aβ) is a 39- to 43-amino-acid peptide that is the major component of neuritic plaques found in Alzheimer's disease (AD). The central region of Aβ plays a crucial role in many of its properties, including aggregation, neurotoxicity, proteolytic processing and interactions with other proteins, such as apolipoprotein E. Two mutations in this region, Ala21→Gly and Glu22→Gln, give rise to early onset forms of disease. We have studied several peptides based on the central region of Aβ in order to clarify the influence of specific amino acid residues on physicochemical behaviour. To avoid difficulties due to oxidation of Met35, the latter was replaced by the amino acid isostere, norleucine (Ahx), giving [Ahx35]Aβ-(25-35)-amide as a prototype structure. To this prototype, addition of pairs of amino acid residues from the sequence of Aβ, forming the corresponding 23-, 21- and 19-35 derivatives, resulted in peptides that aggregated to form fibrils of diameter 6-10 nm. The rate of aggregation was more rapid as peptide length increased. Circular dichroism spectra of aged solutions of peptides revealed that aggregation was accompanied by a transition from random structure to β sheet for some, but not all, peptides. The mutation from Ala to Gly at position 21 increased the rate of aggregation and altered the tendency to adopt secondary structure in the direction away from α helix and towards β sheet. In individuals with the Ala21→Gly mutation, these results would suggest that truncated species with N-termini in the region containing residues 17-20 would be more amyloidogenic than the wild type homologues.

KW - Aβ aggregation

KW - Alzheimer's disease

KW - Amyloid

KW - Secondary structure

UR - http://www.scopus.com/inward/record.url?scp=0032530466&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032530466&partnerID=8YFLogxK

U2 - 10.1046/j.1432-1327.1998.2560560.x

DO - 10.1046/j.1432-1327.1998.2560560.x

M3 - Article

VL - 256

SP - 560

EP - 569

JO - FEBS Journal

JF - FEBS Journal

SN - 1742-464X

IS - 3

ER -