FIGURE 8.

Summary of pathways utilized by aromatic small molecules to remodel Aβ soluble oligomers. Class I molecules remodel Aβ soluble oligomers (ThT- and OC-negative, unstructured as judged by circular dichroism, highly toxic, SDS-soluble) into large aggregates that are SDS-resistant, negative for multiple conformational probes (OC and A11 antibodies, and ThT), unstructured, incompetent for templating Aβ monomers, and non-toxic relative to freshly disaggregated Aβ. In contrast, a Class II molecule selectively converts soluble oligomers into fibrils (which are OC- and ThT-positive, β-sheet rich, SDS-insoluble, A11-negative and mildly toxic). Class III molecules convert soluble oligomers into low molecular species (which are OC-, A11-, and ThT-negative, unstructured, disaggregated as judged by AFM, SDS-soluble and non-toxic relative to freshly disaggregated Aβ). Class IA molecules also convert mature fibrils into large off-pathway structures, and these molecules are inactive against freshly disaggregated Aβ. Class IB molecules convert Aβ monomers into large off-pathway aggregates, and are inactive against fibrils. Class II molecules are inactive against Aβ monomers and fibrils. Class III molecules remodel fibrils into low molecular weight species, and they are inactive against freshly disaggregated Aβ.