Stabilization of nontoxic Ajβ-oligomers: Insights into the mechanism of action of hydroxyquinolines in alzheimer’s disease

Ryan, TM; Roberts, BR; McColl, G; Hare, DJ; Doble, PA; Li, QX; Lind, M; Roberts, AM; Mertens, HDT; Kirb, N; Pham, CLL; Hinds, MG; Adlard, PA; Barnham, KJ; Curtain, CC; Masters, CL

Stabilization of nontoxic Ajβ-oligomers: Insights into the mechanism of action of hydroxyquinolines in alzheimer’s disease

Ryan, TM Roberts, BR McColl, G Hare, DJ

Doble, PA

Li, QX Lind, M Roberts, AM Mertens, HDT Kirb, N Pham, CLL Hinds, MG Adlard, PA Barnham, KJ Curtain, CC Masters, CL

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Publication Type:: Journal Article
Citation:: Journal of Neuroscience, 2015, 35 (7), pp. 2871 - 2884
Issue Date:: 2015-01-01

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Field	Value	Language
dc.contributor.author	Ryan, TM	en_US
dc.contributor.author	Roberts, BR	en_US
dc.contributor.author	McColl, G	en_US
dc.contributor.author	Hare, DJ https://orcid.org/0000-0002-5922-7643	en_US
dc.contributor.author	Doble, PA https://orcid.org/0000-0002-8472-1301	en_US
dc.contributor.author	Li, QX	en_US
dc.contributor.author	Lind, M	en_US
dc.contributor.author	Roberts, AM	en_US
dc.contributor.author	Mertens, HDT	en_US
dc.contributor.author	Kirb, N	en_US
dc.contributor.author	Pham, CLL	en_US
dc.contributor.author	Hinds, MG	en_US
dc.contributor.author	Adlard, PA	en_US
dc.contributor.author	Barnham, KJ	en_US
dc.contributor.author	Curtain, CC	en_US
dc.contributor.author	Masters, CL	en_US
dc.date.issued	2015-01-01	en_US
dc.identifier.citation	Journal of Neuroscience, 2015, 35 (7), pp. 2871 - 2884	en_US
dc.identifier.issn	0270-6474	en_US
dc.identifier.uri	http://hdl.handle.net/10453/35236
dc.identifier.uri	http://hdl.handle.net/10453/35234
dc.description.abstract	©2015 the authors. The extracellular accumulation of amyloid β (A/β) peptides is characteristic of Alzheimer's disease (AD). However, formation of diffusible, oligomeric forms of Aβ, both on and off pathways to amyloid fibrils, is thought to include neurotoxic species responsible for synaptic loss and neurodegeneration, rather than polymeric amyloid aggregates. The 8-hydroxyquinolines (8-HQ) clioquinol (CQ) and PBT2 were developed for their ability to inhibit metal-mediated generation of reactive oxygen species from A/β:Cu complexes and have both undergone preclinical and Phase II clinical development for the treatment of AD. Their respective modes of action are not fully understood and may include both inhibition of Aβ fibrillar polymerization and direct depolymerization of existing Aβ fibrils. In the present study, we find that CQ and PBT2 can interact directly with Aβ and affect its propensity to aggregate. Using a combination of biophysical techniques, we demonstrate that, in the presence of these 8-HQs and in the absence of metal ions, Aβ associates with two 8-HQ molecules and forms a dimer. Furthermore, 8-HQ bind Aβ with an affinity of 1-10 μam and suppress the formation of large (>30kDa) oligomers. The stabilized low molecular weight species are nontoxic. Treatment with 8-HQs also reduces the levels of in vivo soluble oligomers in a Caenorhabditis elegans model of Aβ toxicity. We propose that 8-HQs possess an additional mechanism of action that neutralizes neurotoxic Aβ oligomer formation through stabilization of small (dimeric) nontoxic Aβ conformers.	en_US
dc.relation.ispartof	Journal of Neuroscience	en_US
dc.relation.isbasedon	10.1523/JNEUROSCI.2912-14.2015	en_US
dc.subject.classification	Neurology & Neurosurgery	en_US
dc.subject.mesh	Cerebral Cortex	en_US
dc.subject.mesh	Neurons	en_US
dc.subject.mesh	Cells, Cultured	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Caenorhabditis elegans	en_US
dc.subject.mesh	Alzheimer Disease	en_US
dc.subject.mesh	Thiazoles	en_US
dc.subject.mesh	Hydroxyquinolines	en_US
dc.subject.mesh	Clioquinol	en_US
dc.subject.mesh	Peptide Fragments	en_US
dc.subject.mesh	Microscopy, Electron	en_US
dc.subject.mesh	Enzyme-Linked Immunosorbent Assay	en_US
dc.subject.mesh	Chromatography, Gel	en_US
dc.subject.mesh	Biophysics	en_US
dc.subject.mesh	Protein Binding	en_US
dc.subject.mesh	Scattering, Small Angle	en_US
dc.subject.mesh	Amyloid beta-Peptides	en_US
dc.subject.mesh	Benzothiazoles	en_US
dc.title	Stabilization of nontoxic Ajβ-oligomers: Insights into the mechanism of action of hydroxyquinolines in alzheimer’s disease	en_US
dc.type	Journal Article
utslib.citation.volume	7	en_US
utslib.citation.volume	35	en_US
utslib.for	0301 Analytical Chemistry	en_US
utslib.for	1103 Clinical Sciences	en_US
utslib.for	11 Medical and Health Sciences	en_US
utslib.for	17 Psychology and Cognitive Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CFS - Centre for Forensic Science
utslib.copyright.status	open_access
pubs.issue	7	en_US
pubs.publication-status	Published	en_US
pubs.volume	35	en_US

Abstract:

©2015 the authors. The extracellular accumulation of amyloid β (A/β) peptides is characteristic of Alzheimer's disease (AD). However, formation of diffusible, oligomeric forms of Aβ, both on and off pathways to amyloid fibrils, is thought to include neurotoxic species responsible for synaptic loss and neurodegeneration, rather than polymeric amyloid aggregates. The 8-hydroxyquinolines (8-HQ) clioquinol (CQ) and PBT2 were developed for their ability to inhibit metal-mediated generation of reactive oxygen species from A/β:Cu complexes and have both undergone preclinical and Phase II clinical development for the treatment of AD. Their respective modes of action are not fully understood and may include both inhibition of Aβ fibrillar polymerization and direct depolymerization of existing Aβ fibrils. In the present study, we find that CQ and PBT2 can interact directly with Aβ and affect its propensity to aggregate. Using a combination of biophysical techniques, we demonstrate that, in the presence of these 8-HQs and in the absence of metal ions, Aβ associates with two 8-HQ molecules and forms a dimer. Furthermore, 8-HQ bind Aβ with an affinity of 1-10 μam and suppress the formation of large (>30kDa) oligomers. The stabilized low molecular weight species are nontoxic. Treatment with 8-HQs also reduces the levels of in vivo soluble oligomers in a Caenorhabditis elegans model of Aβ toxicity. We propose that 8-HQs possess an additional mechanism of action that neutralizes neurotoxic Aβ oligomer formation through stabilization of small (dimeric) nontoxic Aβ conformers.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/35234