Protective spin-labeled fluorenes maintain amyloid beta peptide in small oligomers and limit transitions in secondary structure
Abstract
Alzheimer's disease is characterized by the presence of extracellular plaques comprised of amyloid beta (Aβ) peptides. Soluble oligomers of the Aβ peptide underlie a cascade of neuronal loss and dysfunction associated with Alzheimer's disease. Here, single particle analyses of Aβ oligomers in solution by fluorescence correlation spectroscopy (FCS) were used to provide real-time descriptions of how spin-labeled fluorenes (SLFs; bi-functional small molecules that block the toxicity of Aβ) prevent and disrupt oligomeric assemblies of Aβ in solution. Furthermore, the circular dichroism (CD) spectrum of untreated Aβ shows a continuous, progressive change over a 24-hour period, while the spectrum of Aβ treated with SLF remains relatively constant following initial incubation. These findings suggest the conformation of Aβ within the oligomer provides a complementary determinant of Aβ toxicity in addition to oligomer growth and size. Although SLF does not produce a dominant state of secondary structure in Aβ, it does induce a net reduction in beta secondary content compared to untreated samples of Aβ. The FCS results, combined with electron paramagnetic resonance spectroscopy and CD spectroscopy, demonstrate SLFs can inhibit the growth of Aβ oligomers and disrupt existing oligomers, while retaining Aβ as a population of smaller, yet largely disordered oligomers.
- Authors:
-
- Univ. of California, Davis, CA (United States). Dept. of Biochemistry and Molecular Medicine
- Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical and Life Science Directorate
- Univ. of California Davis, Sacramento, CA (United States). MIND Inst. and Dept. of Pathology and Laboratory Medicine
- Univ. of Pecs (Hungary). Inst. of Organic and Medicinal Chemistry
- Publication Date:
- Research Org.:
- Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
- Sponsoring Org.:
- USDOE; National Institutes of Health (NIH); Hungarian Research Fund
- OSTI Identifier:
- 1252634
- Report Number(s):
- LLNL-JRNL-663395-DRAFT
Journal ID: ISSN 1570-9639
- Grant/Contract Number:
- AC52-07NA27344; P30 AG010129; OTKA 104956
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Biochimica et Biophysica Acta. Proteins and Proteomics
- Additional Journal Information:
- Journal Volume: 1854; Journal Issue: 12; Journal ID: ISSN 1570-9639
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Amyloid beta; Oligomer; Spin-labeled fluorene; Secondary structure; Fluorescence correlation spectroscopy; Circular dichroism spectroscopy
Citation Formats
Altman, Robin, Ly, Sonny, Hilt, Silvia, Petrlova, Jitka, Maezawa, Izumi, Kálai, Tamás, Hideg, Kálmán, Jin, Lee-Way, Laurence, Ted A., and Voss, John C. Protective spin-labeled fluorenes maintain amyloid beta peptide in small oligomers and limit transitions in secondary structure. United States: N. p., 2015.
Web. doi:10.1016/j.bbapap.2015.09.002.
Altman, Robin, Ly, Sonny, Hilt, Silvia, Petrlova, Jitka, Maezawa, Izumi, Kálai, Tamás, Hideg, Kálmán, Jin, Lee-Way, Laurence, Ted A., & Voss, John C. Protective spin-labeled fluorenes maintain amyloid beta peptide in small oligomers and limit transitions in secondary structure. United States. https://doi.org/10.1016/j.bbapap.2015.09.002
Altman, Robin, Ly, Sonny, Hilt, Silvia, Petrlova, Jitka, Maezawa, Izumi, Kálai, Tamás, Hideg, Kálmán, Jin, Lee-Way, Laurence, Ted A., and Voss, John C. Mon .
"Protective spin-labeled fluorenes maintain amyloid beta peptide in small oligomers and limit transitions in secondary structure". United States. https://doi.org/10.1016/j.bbapap.2015.09.002. https://www.osti.gov/servlets/purl/1252634.
@article{osti_1252634,
title = {Protective spin-labeled fluorenes maintain amyloid beta peptide in small oligomers and limit transitions in secondary structure},
author = {Altman, Robin and Ly, Sonny and Hilt, Silvia and Petrlova, Jitka and Maezawa, Izumi and Kálai, Tamás and Hideg, Kálmán and Jin, Lee-Way and Laurence, Ted A. and Voss, John C.},
abstractNote = {Alzheimer's disease is characterized by the presence of extracellular plaques comprised of amyloid beta (Aβ) peptides. Soluble oligomers of the Aβ peptide underlie a cascade of neuronal loss and dysfunction associated with Alzheimer's disease. Here, single particle analyses of Aβ oligomers in solution by fluorescence correlation spectroscopy (FCS) were used to provide real-time descriptions of how spin-labeled fluorenes (SLFs; bi-functional small molecules that block the toxicity of Aβ) prevent and disrupt oligomeric assemblies of Aβ in solution. Furthermore, the circular dichroism (CD) spectrum of untreated Aβ shows a continuous, progressive change over a 24-hour period, while the spectrum of Aβ treated with SLF remains relatively constant following initial incubation. These findings suggest the conformation of Aβ within the oligomer provides a complementary determinant of Aβ toxicity in addition to oligomer growth and size. Although SLF does not produce a dominant state of secondary structure in Aβ, it does induce a net reduction in beta secondary content compared to untreated samples of Aβ. The FCS results, combined with electron paramagnetic resonance spectroscopy and CD spectroscopy, demonstrate SLFs can inhibit the growth of Aβ oligomers and disrupt existing oligomers, while retaining Aβ as a population of smaller, yet largely disordered oligomers.},
doi = {10.1016/j.bbapap.2015.09.002},
journal = {Biochimica et Biophysica Acta. Proteins and Proteomics},
number = 12,
volume = 1854,
place = {United States},
year = {Mon Sep 14 00:00:00 EDT 2015},
month = {Mon Sep 14 00:00:00 EDT 2015}
}
Free Publicly Available Full Text
Publisher's Version of Record
Other availability
Search WorldCat to find libraries that may hold this journal
Cited by: 7 works
Citation information provided by
Web of Science
Web of Science
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
A specific amyloid-β protein assembly in the brain impairs memory
journal, March 2006
- Lesné, Sylvain; Koh, Ming Teng; Kotilinek, Linda
- Nature, Vol. 440, Issue 7082
Conserved features of intermediates in amyloid assembly determine their benign or toxic states
journal, June 2012
- Krishnan, R.; Goodman, J. L.; Mukhopadhyay, S.
- Proceedings of the National Academy of Sciences, Vol. 109, Issue 28
Structural Insights into Aβ42 Oligomers Using Site-directed Spin Labeling
journal, June 2013
- Gu, Lei; Liu, Cong; Guo, Zhefeng
- Journal of Biological Chemistry, Vol. 288, Issue 26
Restored degradation of the Alzheimer’s amyloid-β peptide by targeting amyloid formation
journal, March 2009
- Crouch, Peter J.; Tew, Deborah J.; Du, Tai
- Journal of Neurochemistry, Vol. 108, Issue 5
Effects of the Arctic (E 22 →G) Mutation on Amyloid β-Protein Folding: Discrete Molecular Dynamics Study
journal, December 2008
- Lam, A. R.; Teplow, D. B.; Stanley, H. E.
- Journal of the American Chemical Society, Vol. 130, Issue 51
Specific Soluble Oligomers of Amyloid-β Peptide Undergo Replication and Form Non-fibrillar Aggregates in Interfacial Environments
journal, June 2012
- Kumar, Amit; Paslay, Lea C.; Lyons, Daniel
- Journal of Biological Chemistry, Vol. 287, Issue 25
Curcumin Inhibits Formation of Amyloid β Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in Vivo
journal, December 2004
- Yang, Fusheng; Lim, Giselle P.; Begum, Aynun N.
- Journal of Biological Chemistry, Vol. 280, Issue 7
Prefibrillar Amyloid Aggregates Could Be Generic Toxins in Higher Organisms
journal, August 2006
- Baglioni, S.; Casamenti, F.; Bucciantini, M.
- Journal of Neuroscience, Vol. 26, Issue 31
Unique Physicochemical Profile of β-Amyloid Peptide Variant Aβ1–40E22G Protofibrils: Conceivable Neuropathogen in Arctic Mutant Carriers
journal, May 2004
- Päiviö, A.; Jarvet, J.; Gräslund, A.
- Journal of Molecular Biology, Vol. 339, Issue 1
Intrinsic disorder modulates protein self-assembly and aggregation
journal, April 2012
- De Simone, A.; Kitchen, C.; Kwan, A. H.
- Proceedings of the National Academy of Sciences, Vol. 109, Issue 18
Accurate secondary structure prediction and fold recognition for circular dichroism spectroscopy
journal, June 2015
- Micsonai, András; Wien, Frank; Kernya, Linda
- Proceedings of the National Academy of Sciences, Vol. 112, Issue 24
Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis
journal, April 2003
- Kayed, R.
- Science, Vol. 300, Issue 5618
Fluorescence correlation spectroscopy applied to rotational diffusion of macromolecules
journal, February 1976
- Ehrenberg, Måns; Rigler, Rudolf
- Quarterly Reviews of Biophysics, Vol. 9, Issue 1
Solution structure of the Alzheimer amyloid β-peptide (1-42) in an apolar microenvironment: Similarity with a virus fusion domain
journal, October 2002
- Crescenzi, Orlando; Tomaselli, Simona; Guerrini, Remo
- European Journal of Biochemistry, Vol. 269, Issue 22
Small assemblies of unmodified amyloid β-protein are the proximate neurotoxin in Alzheimer’s disease
journal, May 2004
- Klein, W. L.; Stine, W. B.; Teplow, D. B.
- Neurobiology of Aging, Vol. 25, Issue 5
Amyloid β-Protein Fibrillogenesis: STRUCTURE AND BIOLOGICAL ACTIVITY OF PROTOFIBRILLAR INTERMEDIATES
journal, September 1999
- Walsh, Dominic M.; Hartley, Dean M.; Kusumoto, Yoko
- Journal of Biological Chemistry, Vol. 274, Issue 36
A differential association of Apolipoprotein E isoforms with the amyloid-β oligomer in solution: Association of apoE Isoforms with a TOAC-Ab
journal, November 2010
- Petrlova, Jitka; Hong, Hyun-Seok; Bricarello, Daniel A.
- Proteins: Structure, Function, and Bioinformatics, Vol. 79, Issue 2
The Molecular Assembly of Amyloid Aβ Controls Its Neurotoxicity and Binding to Cellular Proteins
journal, September 2011
- Manzoni, Claudia; Colombo, Laura; Bigini, Paolo
- PLoS ONE, Vol. 6, Issue 9
Solution conformations and aggregational properties of synthetic amyloid β-peptides of Alzheimer's disease
journal, June 1992
- Barrow, Colin J.; Yasuda, Akikazu; Kenny, Peter T. M.
- Journal of Molecular Biology, Vol. 225, Issue 4
Inhibition of Alzheimer’s amyloid toxicity with a tricyclic pyrone molecule in vitro and in vivo
journal, February 2009
- Hong, Hyun-Seok; Rana, Sandeep; Barrigan, Lydia
- Journal of Neurochemistry, Vol. 108, Issue 4
Natural oligomers of the amyloid-β protein specifically disrupt cognitive function
journal, December 2004
- Cleary, James P.; Walsh, Dominic M.; Hofmeister, Jacki J.
- Nature Neuroscience, Vol. 8, Issue 1
Blood–brain barrier delivery
journal, January 2007
- Pardridge, William M.
- Drug Discovery Today, Vol. 12, Issue 1-2
Transient dynamics of Aβ contribute to toxicity in Alzheimer’s disease
journal, May 2014
- Hubin, E.; van Nuland, N. A. J.; Broersen, K.
- Cellular and Molecular Life Sciences, Vol. 71, Issue 18
Unraveling the Early Events of Amyloid-β Protein (Aβ) Aggregation: Techniques for the Determination of Aβ Aggregate Size
journal, March 2012
- Pryor, N. Elizabeth; Moss, Melissa A.; Hestekin, Christa N.
- International Journal of Molecular Sciences, Vol. 13, Issue 3
Fibrillar Oligomers Nucleate the Oligomerization of Monomeric Amyloid β but Do Not Seed Fibril Formation
journal, December 2009
- Wu, Jessica W.; Breydo, Leonid; Isas, J. Mario
- Journal of Biological Chemistry, Vol. 285, Issue 9
A Dynamic Relationship between Intracellular and Extracellular Pools of Aβ
journal, January 2006
- Oddo, Salvatore; Caccamo, Antonella; Smith, Ian F.
- The American Journal of Pathology, Vol. 168, Issue 1
Role of Oxidative Stress in the Progression of Alzheimer's Disease
journal, January 2010
- Sultana, Rukhsana; Butterfield, D. Allan
- Journal of Alzheimer's Disease, Vol. 19, Issue 1
Functional Impairment of Microglia Coincides with Beta-Amyloid Deposition in Mice with Alzheimer-Like Pathology
journal, April 2013
- Krabbe, Grietje; Halle, Annett; Matyash, Vitali
- PLoS ONE, Vol. 8, Issue 4
Kinetics of aggregation of synthetic β-amyloid peptide
journal, May 1992
- Tomski, Sharon J.; Murphy, Regina M.
- Archives of Biochemistry and Biophysics, Vol. 294, Issue 2
Polyproline-II Helix in Proteins: Structure and Function
journal, June 2013
- Adzhubei, Alexei A.; Sternberg, Michael J. E.; Makarov, Alexander A.
- Journal of Molecular Biology, Vol. 425, Issue 12
Candidate anti-Aβ fluorene compounds selected from analogs of amyloid imaging agents
journal, October 2010
- Hong, Hyun-Seok; Maezawa, Izumi; Budamagunta, Madhu
- Neurobiology of Aging, Vol. 31, Issue 10
Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory
journal, June 2008
- Shankar, Ganesh M.; Li, Shaomin; Mehta, Tapan H.
- Nature Medicine, Vol. 14, Issue 8
Insight Into the Kinetic of Amyloid β (1–42) Peptide Self-Aggregation: Elucidation of Inhibitors’ Mechanism of Action
journal, November 2007
- Bartolini, Manuela; Bertucci, Carlo; Bolognesi, Maria Laura
- ChemBioChem, Vol. 8, Issue 17
Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils
journal, January 2007
- Cheon, Mookyung; Chang, Iksoo; Mohanty, Sandipan
- PLoS Computational Biology, Vol. 3, Issue 9
The Alzheimer β-peptide shows temperature-dependent transitions between left-handed 31-helix, β-strand and random coil secondary structures: Structural transitions of Alzheimer β-peptide
journal, July 2005
- Danielsson, Jens; Jarvet, Jüri; Damberg, Peter
- FEBS Journal, Vol. 272, Issue 15
The most infectious prion protein particles
journal, September 2005
- Silveira, Jay R.; Raymond, Gregory J.; Hughson, Andrew G.
- Nature, Vol. 437, Issue 7056
Simultaneous measurement of a range of particle sizes during Aβ1–42 fibrillogenesis quantified using fluorescence correlation spectroscopy
journal, May 2014
- Mittag, Judith J.; Milani, Silvia; Walsh, Dominic M.
- Biochemical and Biophysical Research Communications, Vol. 448, Issue 2
Size-dependent neurotoxicity of β-amyloid oligomers
journal, April 2010
- Cizas, Paulius; Budvytyte, Rima; Morkuniene, Ramune
- Archives of Biochemistry and Biophysics, Vol. 496, Issue 2
Rapid induction of Alzheimer A beta amyloid formation by zinc
journal, September 1994
- Bush, A.; Pettingell, W.; Multhaup, G.
- Science, Vol. 265, Issue 5177
The structural basis of protein folding and its links with human disease
journal, February 2001
- Dobson, Christopher M.
- Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, Vol. 356, Issue 1406
Statistical accuracy in fluorescence correlation spectroscopy
journal, December 1974
- Koppel, Dennis E.
- Physical Review A, Vol. 10, Issue 6
Alternate Aggregation Pathways of the Alzheimer β-Amyloid Peptide
journal, November 2000
- Huang, T. H. Jackson; Yang, Dun-Sheng; Fraser, Paul E.
- Journal of Biological Chemistry, Vol. 275, Issue 46
Attenuation of the Early Events of α-Synuclein Aggregation: A Fluorescence Correlation Spectroscopy and Laser Scanning Microscopy Study in the Presence of Surface-Coated Fe 3 O 4 Nanoparticles
journal, January 2015
- Joshi, Nidhi; Basak, Sujit; Kundu, Sangeeta
- Langmuir, Vol. 31, Issue 4
Assembly and aggregation properties of synthetic Alzheimer's A4/beta amyloid peptide analogs.
journal, January 1992
- Burdick, D.; Soreghan, B.; Kwon, M.
- Journal of Biological Chemistry, Vol. 267, Issue 1
Detection and Characterization of Aggregates, Prefibrillar Amyloidogenic Oligomers, and Protofibrils Using Fluorescence Spectroscopy
journal, June 2005
- Lindgren, Mikael; Sörgjerd, Karin; Hammarström, Per
- Biophysical Journal, Vol. 88, Issue 6
Zinc-Amyloid β Interactions on a Millisecond Time-Scale Stabilize Non-fibrillar Alzheimer-Related Species
journal, January 2008
- Noy, Dror; Solomonov, Inna; Sinkevich, Ory
- Journal of the American Chemical Society, Vol. 130, Issue 4
Bridging the gap: From protein misfolding to protein misfolding diseases
journal, June 2009
- Luheshi, Leila M.; Dobson, Christopher M.
- FEBS Letters, Vol. 583, Issue 16
Structural and Dynamic Features of Alzheimer's Aβ Peptide in Amyloid Fibrils Studied by Site-directed Spin Labeling
journal, August 2002
- Török, Marianna; Milton, Saskia; Kayed, Rakez
- Journal of Biological Chemistry, Vol. 277, Issue 43
Interactions of Zn(ii) and Cu(ii) ions with Alzheimer's amyloid-beta peptide. Metal ion binding, contribution to fibrillization and toxicity
journal, January 2011
- Tõugu, Vello; Tiiman, Ann; Palumaa, Peep
- Metallomics, Vol. 3, Issue 3
Structural composition of betaI- and betaII-proteins
journal, February 2003
- Sreerama, N.
- Protein Science, Vol. 12, Issue 2
Synthesis and study of 2-amino-7-bromofluorenes modified with nitroxides and their precursors as dual anti-amyloid and antioxidant active compounds
journal, April 2011
- Kálai, Tamás; Petrlova, Jitka; Balog, Mária
- European Journal of Medicinal Chemistry, Vol. 46, Issue 4
The Influence of Spin-Labeled Fluorene Compounds on the Assembly and Toxicity of the Aβ Peptide
journal, April 2012
- Petrlova, Jitka; Kálai, Tamás; Maezawa, Izumi
- PLoS ONE, Vol. 7, Issue 4
Zinc Lowers Amyloid-β Toxicity by Selectively Precipitating Aggregation Intermediates
journal, August 2007
- Garai, K.; Sahoo, B.; Kaushalya, S. K.
- Biochemistry, Vol. 46, Issue 37
Disruption of zinc homeostasis and the pathogenesis of senile dementia
journal, January 2014
- Kawahara, Masahiro; Mizuno, Dai; Koyama, Hironari
- Metallomics, Vol. 6, Issue 2
Tetracycline prevents Aβ oligomer toxicity through an atypical supramolecular interaction
journal, January 2011
- Airoldi, Cristina; Colombo, Laura; Manzoni, Claudia
- Org. Biomol. Chem., Vol. 9, Issue 2
ANS Binding Reveals Common Features of Cytotoxic Amyloid Species
journal, June 2010
- Bolognesi, Benedetta; Kumita, Janet R.; Barros, Teresa P.
- ACS Chemical Biology, Vol. 5, Issue 8
The role of astrocytes in amyloid β-protein toxicity and clearance
journal, July 2012
- Thal, Dietmar Rudolf
- Experimental Neurology, Vol. 236, Issue 1
Aggregation and secondary structure of synthetic amyloid βA4 peptides of Alzheimer's disease
journal, March 1991
- Hilbich, Caroline; Kisters-Woike, Brigitte; Reed, Jennifer
- Journal of Molecular Biology, Vol. 218, Issue 1
Thermodynamic Fluctuations in a Reacting System—Measurement by Fluorescence Correlation Spectroscopy
journal, September 1972
- Magde, Douglas; Elson, Elliot; Webb, W. W.
- Physical Review Letters, Vol. 29, Issue 11
Rational Design of β-Sheet Ligands Against Aβ 42 -Induced Toxicity
journal, March 2011
- Hochdörffer, Katrin; März-Berberich, Julia; Nagel-Steger, Luitgard
- Journal of the American Chemical Society, Vol. 133, Issue 12
Nature of the Amyloid-β Monomer and the Monomer-Oligomer Equilibrium
journal, April 2011
- Nag, Suman; Sarkar, Bidyut; Bandyopadhyay, Arkarup
- Journal of Biological Chemistry, Vol. 286, Issue 16
Proliferation of amyloid- 42 aggregates occurs through a secondary nucleation mechanism
journal, May 2013
- Cohen, S. I. A.; Linse, S.; Luheshi, L. M.
- Proceedings of the National Academy of Sciences, Vol. 110, Issue 24
Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases
journal, April 2002
- Bucciantini, Monica; Giannoni, Elisa; Chiti, Fabrizio
- Nature, Vol. 416, Issue 6880
Modulation Filtering Enables Removal of Spikes in Fluorescence Correlation Spectroscopy Measurements without Affecting the Temporal Information
journal, June 2009
- Persson, Gustav; Thyberg, Per; Sandén, Tor
- The Journal of Physical Chemistry B, Vol. 113, Issue 25
Dimethylamino-fluorenes: ligands for detecting β-amyloid plaques in the brain
journal, August 2003
- Lee, Chi-Wan; Kung, Mei-Ping; Hou, Catherine
- Nuclear Medicine and Biology, Vol. 30, Issue 6
Designing conditions for in vitro formation of amyloid protofilaments and fibrils
journal, March 1999
- Chiti, F.; Webster, P.; Taddei, N.
- Proceedings of the National Academy of Sciences, Vol. 96, Issue 7
On the subject of rigor in the study of amyloid β-protein assembly
journal, January 2013
- Teplow, David B.
- Alzheimer's Research & Therapy, Vol. 5, Issue 4
A causative link between the structure of aberrant protein oligomers and their toxicity
journal, January 2010
- Campioni, Silvia; Mannini, Benedetta; Zampagni, Mariagioia
- Nature Chemical Biology, Vol. 6, Issue 2
Combining the rapid MTT formazan exocytosis assay and the MC65 protection assay led to the discovery of carbazole analogs as small molecule inhibitors of Aβ oligomer-induced cytotoxicity
journal, January 2007
- Hong, Hyun-Seok; Maezawa, Izumi; Yao, Nianhuan
- Brain Research, Vol. 1130
Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability
journal, August 2002
- Dahlgren, Karie N.; Manelli, Arlene M.; Stine, W. Blaine
- Journal of Biological Chemistry, Vol. 277, Issue 35
Amyloid-beta aggregation: selective inhibition of aggregation in mixtures of amyloid with different chain lengths
journal, September 1994
- Snyder, S. W.; Ladror, U. S.; Wade, W. S.
- Biophysical Journal, Vol. 67, Issue 3
Works referencing / citing this record:
A Bifunctional Anti-Amyloid Blocks Oxidative Stress and the Accumulation of Intraneuronal Amyloid-Beta
journal, August 2018
- Hilt, Silvia; Altman, Robin; Kálai, Tamás
- Molecules, Vol. 23, Issue 8