Stabilization of Nontoxic A -Oligomers: Insights into the Mechanism of Action of Hydroxyquinolines in Alzheimer's Disease
Journal of Neuroscience
The extracellular accumulation of amyloid ␤ (A␤) peptides is characteristic of Alzheimer's disease (AD). However, formation of diffusible, oligomeric forms of A␤, 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
... e oxygen species from A␤: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 A␤ fibrillar polymerization and direct depolymerization of existing A␤ fibrils. In the present study, we find that CQ and PBT2 can interact directly with A␤ 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, A␤ associates with two 8-HQ molecules and forms a dimer. Furthermore, 8-HQ bind A␤ with an affinity of 1-10 M and suppress the formation of large (Ͼ30 kDa) 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 A␤ toxicity. We propose that 8-HQs possess an additional mechanism of action that neutralizes neurotoxic A␤ oligomer formation through stabilization of small (dimeric) nontoxic A␤ conformers.