Binding of apolipoprotein E inhibits the oligomer growth of amyloid-β peptide in solution as determined by fluorescence cross-correlation spectroscopy

Sonny Ly, Robin Altman, Jitka Petrlova, Yu Lin, Silvia Hilt, Thomas R Huser, Ted A. Laurence, John C Voss

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

One of the primary neuropathological hallmarks of Alzheimer disease is the presence of extracellular amyloid plaques resulting from the aggregation of amyloid-β (Aβ) peptides. The intrinsic disorder of the Aβ peptide drives self-association and progressive reordering of the conformation in solution, and this dynamic distribution of Aβ complicates biophysical studies. This property poses a challenge for understanding the interaction of Aβ with apolipoprotein E (apoE). ApoE plays a pivotal role in the aggregation and clearance of Aβ peptides in the brain, and the ε4 allele of APOE is the most significant known genetic modulator of Alzheimer risk. Understanding the interaction between apoE and Aβ will provide insight into the mechanism by which different apoE isoforms determine Alzheimer disease risk. Here we applied alternating laser excitation fluorescence cross-correlation spectroscopy to observe the single molecule interaction of Aβ with apoE in the hydrated state. The diffusion time of freely diffusing Aβ in the absence of apoE shows significant self-aggregation, whereas in the presence of apoE, binding of the protein results in a more stable complex. These results show that apoE slows down the oligomerization of Aβ in solution and provide direct insight into the process by which apoE influences the deposition and clearance of Aβ peptides in the brain. Furthermore, by developing an approach to remove signals arising from very large Aβ aggregates, we show that real-time single particle observations provide access to information regarding the fraction of apoE bound and the stoichiometry of apoE and Aβ in the complex.

Original languageEnglish (US)
Pages (from-to)11628-11635
Number of pages8
JournalJournal of Biological Chemistry
Volume288
Issue number17
DOIs
StatePublished - Apr 26 2013

Fingerprint

Apolipoproteins E
Oligomers
Amyloid
Spectrum Analysis
Fluorescence
Spectroscopy
Peptides
Growth
Apolipoproteins A
Agglomeration
Brain
Alzheimer Disease
Access to Information
Oligomerization
Laser excitation
Amyloid Plaques
Stoichiometry
Modulators
Conformations
Carrier Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Binding of apolipoprotein E inhibits the oligomer growth of amyloid-β peptide in solution as determined by fluorescence cross-correlation spectroscopy. / Ly, Sonny; Altman, Robin; Petrlova, Jitka; Lin, Yu; Hilt, Silvia; Huser, Thomas R; Laurence, Ted A.; Voss, John C.

In: Journal of Biological Chemistry, Vol. 288, No. 17, 26.04.2013, p. 11628-11635.

Research output: Contribution to journalArticle

Ly, Sonny ; Altman, Robin ; Petrlova, Jitka ; Lin, Yu ; Hilt, Silvia ; Huser, Thomas R ; Laurence, Ted A. ; Voss, John C. / Binding of apolipoprotein E inhibits the oligomer growth of amyloid-β peptide in solution as determined by fluorescence cross-correlation spectroscopy. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 17. pp. 11628-11635.
@article{ffba50f33102461793875965713d54b9,
title = "Binding of apolipoprotein E inhibits the oligomer growth of amyloid-β peptide in solution as determined by fluorescence cross-correlation spectroscopy",
abstract = "One of the primary neuropathological hallmarks of Alzheimer disease is the presence of extracellular amyloid plaques resulting from the aggregation of amyloid-β (Aβ) peptides. The intrinsic disorder of the Aβ peptide drives self-association and progressive reordering of the conformation in solution, and this dynamic distribution of Aβ complicates biophysical studies. This property poses a challenge for understanding the interaction of Aβ with apolipoprotein E (apoE). ApoE plays a pivotal role in the aggregation and clearance of Aβ peptides in the brain, and the ε4 allele of APOE is the most significant known genetic modulator of Alzheimer risk. Understanding the interaction between apoE and Aβ will provide insight into the mechanism by which different apoE isoforms determine Alzheimer disease risk. Here we applied alternating laser excitation fluorescence cross-correlation spectroscopy to observe the single molecule interaction of Aβ with apoE in the hydrated state. The diffusion time of freely diffusing Aβ in the absence of apoE shows significant self-aggregation, whereas in the presence of apoE, binding of the protein results in a more stable complex. These results show that apoE slows down the oligomerization of Aβ in solution and provide direct insight into the process by which apoE influences the deposition and clearance of Aβ peptides in the brain. Furthermore, by developing an approach to remove signals arising from very large Aβ aggregates, we show that real-time single particle observations provide access to information regarding the fraction of apoE bound and the stoichiometry of apoE and Aβ in the complex.",
author = "Sonny Ly and Robin Altman and Jitka Petrlova and Yu Lin and Silvia Hilt and Huser, {Thomas R} and Laurence, {Ted A.} and Voss, {John C}",
year = "2013",
month = "4",
day = "26",
doi = "10.1074/jbc.M112.411900",
language = "English (US)",
volume = "288",
pages = "11628--11635",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "17",

}

TY - JOUR

T1 - Binding of apolipoprotein E inhibits the oligomer growth of amyloid-β peptide in solution as determined by fluorescence cross-correlation spectroscopy

AU - Ly, Sonny

AU - Altman, Robin

AU - Petrlova, Jitka

AU - Lin, Yu

AU - Hilt, Silvia

AU - Huser, Thomas R

AU - Laurence, Ted A.

AU - Voss, John C

PY - 2013/4/26

Y1 - 2013/4/26

N2 - One of the primary neuropathological hallmarks of Alzheimer disease is the presence of extracellular amyloid plaques resulting from the aggregation of amyloid-β (Aβ) peptides. The intrinsic disorder of the Aβ peptide drives self-association and progressive reordering of the conformation in solution, and this dynamic distribution of Aβ complicates biophysical studies. This property poses a challenge for understanding the interaction of Aβ with apolipoprotein E (apoE). ApoE plays a pivotal role in the aggregation and clearance of Aβ peptides in the brain, and the ε4 allele of APOE is the most significant known genetic modulator of Alzheimer risk. Understanding the interaction between apoE and Aβ will provide insight into the mechanism by which different apoE isoforms determine Alzheimer disease risk. Here we applied alternating laser excitation fluorescence cross-correlation spectroscopy to observe the single molecule interaction of Aβ with apoE in the hydrated state. The diffusion time of freely diffusing Aβ in the absence of apoE shows significant self-aggregation, whereas in the presence of apoE, binding of the protein results in a more stable complex. These results show that apoE slows down the oligomerization of Aβ in solution and provide direct insight into the process by which apoE influences the deposition and clearance of Aβ peptides in the brain. Furthermore, by developing an approach to remove signals arising from very large Aβ aggregates, we show that real-time single particle observations provide access to information regarding the fraction of apoE bound and the stoichiometry of apoE and Aβ in the complex.

AB - One of the primary neuropathological hallmarks of Alzheimer disease is the presence of extracellular amyloid plaques resulting from the aggregation of amyloid-β (Aβ) peptides. The intrinsic disorder of the Aβ peptide drives self-association and progressive reordering of the conformation in solution, and this dynamic distribution of Aβ complicates biophysical studies. This property poses a challenge for understanding the interaction of Aβ with apolipoprotein E (apoE). ApoE plays a pivotal role in the aggregation and clearance of Aβ peptides in the brain, and the ε4 allele of APOE is the most significant known genetic modulator of Alzheimer risk. Understanding the interaction between apoE and Aβ will provide insight into the mechanism by which different apoE isoforms determine Alzheimer disease risk. Here we applied alternating laser excitation fluorescence cross-correlation spectroscopy to observe the single molecule interaction of Aβ with apoE in the hydrated state. The diffusion time of freely diffusing Aβ in the absence of apoE shows significant self-aggregation, whereas in the presence of apoE, binding of the protein results in a more stable complex. These results show that apoE slows down the oligomerization of Aβ in solution and provide direct insight into the process by which apoE influences the deposition and clearance of Aβ peptides in the brain. Furthermore, by developing an approach to remove signals arising from very large Aβ aggregates, we show that real-time single particle observations provide access to information regarding the fraction of apoE bound and the stoichiometry of apoE and Aβ in the complex.

UR - http://www.scopus.com/inward/record.url?scp=84876894324&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84876894324&partnerID=8YFLogxK

U2 - 10.1074/jbc.M112.411900

DO - 10.1074/jbc.M112.411900

M3 - Article

C2 - 23430745

AN - SCOPUS:84876894324

VL - 288

SP - 11628

EP - 11635

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 17

ER -