Targeting the neurotoxic species in Alzheimer's disease: inhibitors of Aβ oligomerization

In the past two decades, a large body of evidence has established a causative role for the beta-amyloid peptide (Abeta) in Alzheimer's disease (AD). However, recent debate has focused on whether amyloid fibrils or soluble oligomers of Abeta are the main neurotoxic species that contribute to neurodegeneration and dementia. Considerable early evidence has indicated that amyloid fibrils are toxic, but some recent studies support the notion that Abeta oligomers are the primary neurotoxins. While this crucial aspect of AD pathogenesis remains controversial, effective therapeutic strategies should ideally target both oligomeric and fibrillar species of Abeta. Here, we describe the anti-amyloidogenic and neuroprotective actions of some di- and tri-substituted aromatic compounds. Inhibition of the formation of soluble Abeta oligomers was monitored using a specific antibody-based assay that discriminates between Abeta oligomers and monomers. Thioflavin T and electron microscopy were used to screen for inhibitors of fibril formation. Taken together, these results led to the identification of compounds that more effectively block Abeta oligomerization than fibrillization. It is significant that such compounds completely blocked the neurotoxicity of Abeta to rat hippocampal neurons in culture. These findings provide a basis for the development of novel small molecule Abeta inhibitors with potential applications in AD.