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