skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Protective spin-labeled fluorenes maintain amyloid beta peptide in small oligomers and limit transitions in secondary structure

Journal Article · · Biochimica et Biophysica Acta. Proteins and Proteomics
 [1];  [2];  [1];  [1];  [3];  [4];  [4];  [3];  [1];  [1]
  1. Univ. of California, Davis, CA (United States). Dept. of Biochemistry and Molecular Medicine
  2. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Physical and Life Science Directorate
  3. Univ. of California Davis, Sacramento, CA (United States). MIND Inst. and Dept. of Pathology and Laboratory Medicine
  4. Univ. of Pecs (Hungary). Inst. of Organic and Medicinal Chemistry
+ Show Author Affiliations

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.

Research Organization:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Organization:
USDOE; National Institutes of Health (NIH); Hungarian Research Fund
Grant/Contract Number:
AC52-07NA27344; P30 AG010129; OTKA 104956
OSTI ID:
1252634
Report Number(s):
LLNL-JRNL-663395-DRAFT
Journal Information:
Biochimica et Biophysica Acta. Proteins and Proteomics, Vol. 1854, Issue 12; ISSN 1570-9639
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 7 works
Citation information provided by
Web of Science

References (71)

A specific amyloid-β protein assembly in the brain impairs memory journal March 2006
Conserved features of intermediates in amyloid assembly determine their benign or toxic states journal June 2012
Structural Insights into Aβ42 Oligomers Using Site-directed Spin Labeling journal June 2013
Restored degradation of the Alzheimer’s amyloid-β peptide by targeting amyloid formation journal March 2009
Effects of the Arctic (E 22 →G) Mutation on Amyloid β-Protein Folding: Discrete Molecular Dynamics Study journal December 2008
Specific Soluble Oligomers of Amyloid-β Peptide Undergo Replication and Form Non-fibrillar Aggregates in Interfacial Environments journal June 2012
Curcumin Inhibits Formation of Amyloid β Oligomers and Fibrils, Binds Plaques, and Reduces Amyloid in Vivo journal December 2004
Prefibrillar Amyloid Aggregates Could Be Generic Toxins in Higher Organisms journal August 2006
Unique Physicochemical Profile of β-Amyloid Peptide Variant Aβ1–40E22G Protofibrils: Conceivable Neuropathogen in Arctic Mutant Carriers journal May 2004
Intrinsic disorder modulates protein self-assembly and aggregation journal April 2012
Accurate secondary structure prediction and fold recognition for circular dichroism spectroscopy journal June 2015
Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis journal April 2003
Fluorescence correlation spectroscopy applied to rotational diffusion of macromolecules journal February 1976
Solution structure of the Alzheimer amyloid β-peptide (1-42) in an apolar microenvironment: Similarity with a virus fusion domain journal October 2002
Small assemblies of unmodified amyloid β-protein are the proximate neurotoxin in Alzheimer’s disease journal May 2004
Amyloid β-Protein Fibrillogenesis: STRUCTURE AND BIOLOGICAL ACTIVITY OF PROTOFIBRILLAR INTERMEDIATES journal September 1999
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
The Molecular Assembly of Amyloid Aβ Controls Its Neurotoxicity and Binding to Cellular Proteins journal September 2011
Solution conformations and aggregational properties of synthetic amyloid β-peptides of Alzheimer's disease journal June 1992
Inhibition of Alzheimer’s amyloid toxicity with a tricyclic pyrone molecule in vitro and in vivo journal February 2009
Natural oligomers of the amyloid-β protein specifically disrupt cognitive function journal December 2004
Blood–brain barrier delivery journal January 2007
Transient dynamics of Aβ contribute to toxicity in Alzheimer’s disease journal May 2014
Unraveling the Early Events of Amyloid-β Protein (Aβ) Aggregation: Techniques for the Determination of Aβ Aggregate Size journal March 2012
Fibrillar Oligomers Nucleate the Oligomerization of Monomeric Amyloid β but Do Not Seed Fibril Formation journal December 2009
A Dynamic Relationship between Intracellular and Extracellular Pools of Aβ journal January 2006
Role of Oxidative Stress in the Progression of Alzheimer's Disease journal January 2010
Functional Impairment of Microglia Coincides with Beta-Amyloid Deposition in Mice with Alzheimer-Like Pathology journal April 2013
Kinetics of aggregation of synthetic β-amyloid peptide journal May 1992
Polyproline-II Helix in Proteins: Structure and Function journal June 2013
Candidate anti-Aβ fluorene compounds selected from analogs of amyloid imaging agents journal October 2010
Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory journal June 2008
Insight Into the Kinetic of Amyloid β (1–42) Peptide Self-Aggregation: Elucidation of Inhibitors’ Mechanism of Action journal November 2007
Structural Reorganisation and Potential Toxicity of Oligomeric Species Formed during the Assembly of Amyloid Fibrils journal January 2007
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
The most infectious prion protein particles journal September 2005
Simultaneous measurement of a range of particle sizes during Aβ1–42 fibrillogenesis quantified using fluorescence correlation spectroscopy journal May 2014
Size-dependent neurotoxicity of β-amyloid oligomers journal April 2010
Rapid induction of Alzheimer A beta amyloid formation by zinc journal September 1994
The structural basis of protein folding and its links with human disease journal February 2001
Statistical accuracy in fluorescence correlation spectroscopy journal December 1974
Alternate Aggregation Pathways of the Alzheimer β-Amyloid Peptide journal November 2000
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
Assembly and aggregation properties of synthetic Alzheimer's A4/beta amyloid peptide analogs. journal January 1992
Detection and Characterization of Aggregates, Prefibrillar Amyloidogenic Oligomers, and Protofibrils Using Fluorescence Spectroscopy journal June 2005
Zinc-Amyloid β Interactions on a Millisecond Time-Scale Stabilize Non-fibrillar Alzheimer-Related Species journal January 2008
Bridging the gap: From protein misfolding to protein misfolding diseases journal June 2009
Structural and Dynamic Features of Alzheimer's Aβ Peptide in Amyloid Fibrils Studied by Site-directed Spin Labeling journal August 2002
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
Structural composition of betaI- and betaII-proteins journal February 2003
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
The Influence of Spin-Labeled Fluorene Compounds on the Assembly and Toxicity of the Aβ Peptide journal April 2012
Zinc Lowers Amyloid-β Toxicity by Selectively Precipitating Aggregation Intermediates journal August 2007
Disruption of zinc homeostasis and the pathogenesis of senile dementia journal January 2014
Tetracycline prevents Aβ oligomer toxicity through an atypical supramolecular interaction journal January 2011
ANS Binding Reveals Common Features of Cytotoxic Amyloid Species journal June 2010
The role of astrocytes in amyloid β-protein toxicity and clearance journal July 2012
Aggregation and secondary structure of synthetic amyloid βA4 peptides of Alzheimer's disease journal March 1991
Thermodynamic Fluctuations in a Reacting System—Measurement by Fluorescence Correlation Spectroscopy journal September 1972
Rational Design of β-Sheet Ligands Against Aβ 42 -Induced Toxicity
  • Hochdörffer, Katrin; März-Berberich, Julia; Nagel-Steger, Luitgard
  • Journal of the American Chemical Society, Vol. 133, Issue 12 https://doi.org/10.1021/ja107675n
journal March 2011
Nature of the Amyloid-β Monomer and the Monomer-Oligomer Equilibrium journal April 2011
Proliferation of amyloid- 42 aggregates occurs through a secondary nucleation mechanism journal May 2013
Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases journal April 2002
Modulation Filtering Enables Removal of Spikes in Fluorescence Correlation Spectroscopy Measurements without Affecting the Temporal Information journal June 2009
Dimethylamino-fluorenes: ligands for detecting β-amyloid plaques in the brain journal August 2003
Designing conditions for in vitro formation of amyloid protofilaments and fibrils journal March 1999
On the subject of rigor in the study of amyloid β-protein assembly journal January 2013
A causative link between the structure of aberrant protein oligomers and their toxicity journal January 2010
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
Oligomeric and Fibrillar Species of Amyloid-β Peptides Differentially Affect Neuronal Viability journal August 2002
Amyloid-beta aggregation: selective inhibition of aggregation in mixtures of amyloid with different chain lengths journal September 1994

Cited By (1)

A Bifunctional Anti-Amyloid Blocks Oxidative Stress and the Accumulation of Intraneuronal Amyloid-Beta journal August 2018

Similar Records

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
Amyloid beta
Oligomer
Spin-labeled fluorene
Secondary structure
Fluorescence correlation spectroscopy
Circular dichroism spectroscopy