Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity

Kenji Usui, John D. Hulleman, Johan F. Paulsson, Sarah J. Siegel, Evan T. Powers, Jeffery W. Kelly

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Accumulation of amyloid β-peptide (Aβ) and tau aggregates, possibly linked to age-associated deficiencies in protein homeostasis, appear to cause Alzheimer's disease. Schiff-base formation between Aβ and the aldehyde-bearing cholesterol oxidation product 3-β-hydroxy-5-oxo-5,6- secocholestan-6-al is known to increase Aβ amyloidogenicity. Here, we synthesized Aβ variants site-specifically modified with the cholesterol aldehyde at Asp-1, Lys-16, or Lys-28, rather than studying mixtures. These distinct modifications have a similar effect on the thermodynamic propensity for aggregation, enabling aggregation at low concentrations. In contrast, the modification site differentially influences the aggregation kinetics; Lys-16-modified Aβ formed amorphous aggregates fastest and at the lowest concentration (within 2 h at a concentration of 20 nM), followed by the Lys-28 and Asp-1 conjugates. Also, the aggregates resulting from Aβ Lys-16 cholesterol aldehyde conjugation were more toxic to primary rat cortical neurons than treatment with unmodified Aβ under identical conditions and at the same concentration. Our results show that Aβ modification by cholesterol derivatives, especially at Lys-16, renders it kinetically and thermodynamically competent to form neurotoxic aggregates at concentrations approaching the physiologic concentration of Aβ.

Original languageEnglish (US)
Pages (from-to)18563-18568
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number44
DOIs
StatePublished - Nov 3 2009

Fingerprint

Cholesterol
Aldehydes
Peptides
Protein Deficiency
Schiff Bases
Poisons
Thermodynamics
Amyloid
Alzheimer Disease
Homeostasis
Neurons

Keywords

  • Amyloid
  • Oxidative stress
  • Oxidized metabolite
  • Protein misfolding

ASJC Scopus subject areas

  • General

Cite this

Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity. / Usui, Kenji; Hulleman, John D.; Paulsson, Johan F.; Siegel, Sarah J.; Powers, Evan T.; Kelly, Jeffery W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 44, 03.11.2009, p. 18563-18568.

Research output: Contribution to journalArticle

@article{af023b64beeb41268bd930f8e66d3c44,
title = "Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity",
abstract = "Accumulation of amyloid β-peptide (Aβ) and tau aggregates, possibly linked to age-associated deficiencies in protein homeostasis, appear to cause Alzheimer's disease. Schiff-base formation between Aβ and the aldehyde-bearing cholesterol oxidation product 3-β-hydroxy-5-oxo-5,6- secocholestan-6-al is known to increase Aβ amyloidogenicity. Here, we synthesized Aβ variants site-specifically modified with the cholesterol aldehyde at Asp-1, Lys-16, or Lys-28, rather than studying mixtures. These distinct modifications have a similar effect on the thermodynamic propensity for aggregation, enabling aggregation at low concentrations. In contrast, the modification site differentially influences the aggregation kinetics; Lys-16-modified Aβ formed amorphous aggregates fastest and at the lowest concentration (within 2 h at a concentration of 20 nM), followed by the Lys-28 and Asp-1 conjugates. Also, the aggregates resulting from Aβ Lys-16 cholesterol aldehyde conjugation were more toxic to primary rat cortical neurons than treatment with unmodified Aβ under identical conditions and at the same concentration. Our results show that Aβ modification by cholesterol derivatives, especially at Lys-16, renders it kinetically and thermodynamically competent to form neurotoxic aggregates at concentrations approaching the physiologic concentration of Aβ.",
keywords = "Aβ, Amyloid, Oxidative stress, Oxidized metabolite, Protein misfolding",
author = "Kenji Usui and Hulleman, {John D.} and Paulsson, {Johan F.} and Siegel, {Sarah J.} and Powers, {Evan T.} and Kelly, {Jeffery W.}",
year = "2009",
month = "11",
day = "3",
doi = "10.1073/pnas.0804758106",
language = "English (US)",
volume = "106",
pages = "18563--18568",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "44",

}

TY - JOUR

T1 - Site-specific modification of Alzheimer's peptides by cholesterol oxidation products enhances aggregation energetics and neurotoxicity

AU - Usui, Kenji

AU - Hulleman, John D.

AU - Paulsson, Johan F.

AU - Siegel, Sarah J.

AU - Powers, Evan T.

AU - Kelly, Jeffery W.

PY - 2009/11/3

Y1 - 2009/11/3

N2 - Accumulation of amyloid β-peptide (Aβ) and tau aggregates, possibly linked to age-associated deficiencies in protein homeostasis, appear to cause Alzheimer's disease. Schiff-base formation between Aβ and the aldehyde-bearing cholesterol oxidation product 3-β-hydroxy-5-oxo-5,6- secocholestan-6-al is known to increase Aβ amyloidogenicity. Here, we synthesized Aβ variants site-specifically modified with the cholesterol aldehyde at Asp-1, Lys-16, or Lys-28, rather than studying mixtures. These distinct modifications have a similar effect on the thermodynamic propensity for aggregation, enabling aggregation at low concentrations. In contrast, the modification site differentially influences the aggregation kinetics; Lys-16-modified Aβ formed amorphous aggregates fastest and at the lowest concentration (within 2 h at a concentration of 20 nM), followed by the Lys-28 and Asp-1 conjugates. Also, the aggregates resulting from Aβ Lys-16 cholesterol aldehyde conjugation were more toxic to primary rat cortical neurons than treatment with unmodified Aβ under identical conditions and at the same concentration. Our results show that Aβ modification by cholesterol derivatives, especially at Lys-16, renders it kinetically and thermodynamically competent to form neurotoxic aggregates at concentrations approaching the physiologic concentration of Aβ.

AB - Accumulation of amyloid β-peptide (Aβ) and tau aggregates, possibly linked to age-associated deficiencies in protein homeostasis, appear to cause Alzheimer's disease. Schiff-base formation between Aβ and the aldehyde-bearing cholesterol oxidation product 3-β-hydroxy-5-oxo-5,6- secocholestan-6-al is known to increase Aβ amyloidogenicity. Here, we synthesized Aβ variants site-specifically modified with the cholesterol aldehyde at Asp-1, Lys-16, or Lys-28, rather than studying mixtures. These distinct modifications have a similar effect on the thermodynamic propensity for aggregation, enabling aggregation at low concentrations. In contrast, the modification site differentially influences the aggregation kinetics; Lys-16-modified Aβ formed amorphous aggregates fastest and at the lowest concentration (within 2 h at a concentration of 20 nM), followed by the Lys-28 and Asp-1 conjugates. Also, the aggregates resulting from Aβ Lys-16 cholesterol aldehyde conjugation were more toxic to primary rat cortical neurons than treatment with unmodified Aβ under identical conditions and at the same concentration. Our results show that Aβ modification by cholesterol derivatives, especially at Lys-16, renders it kinetically and thermodynamically competent to form neurotoxic aggregates at concentrations approaching the physiologic concentration of Aβ.

KW - Aβ

KW - Amyloid

KW - Oxidative stress

KW - Oxidized metabolite

KW - Protein misfolding

UR - http://www.scopus.com/inward/record.url?scp=73249128637&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73249128637&partnerID=8YFLogxK

U2 - 10.1073/pnas.0804758106

DO - 10.1073/pnas.0804758106

M3 - Article

VL - 106

SP - 18563

EP - 18568

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 44

ER -