Growing evidence suggests that on-pathway amyloid-â (Aâ) oligomers are primary neurotoxic species and have a direct correlation with the onset of Alzheimer's disease (AD). One promising therapeutic strategy to block AD progression is to reduce the levels of these neurotoxic Aâ species using small molecules. While several compounds have been shown to modulate Aâ aggregation, compounds with such activity combined with safety and high blood-brain barrier (BBB) permeability have yet to be reported. Brilliant Blue G (BBG) is a close structural analogue of a U.S. Food and Drug Administration (FDA)-approved food dye and has recently garnered prominent attention as a potential drug to treat spinal cord injury due to its neuroprotective effects along with BBB permeability and high degree of safety. In this work, we demonstrate that BBG is an effective Aâ aggregation modulator, which reduces Aâ-associated cytotoxicity in a dose-dependent manner by promoting the formation of off-pathway, nontoxic aggregates. Comparative studies of BBG and three structural analogues, Brilliant Blue R (BBR), Brilliant Blue FCF (BBF), and Fast Green FCF (FGF), revealed that BBG is most effective, BBR is moderately effective, and BBF and FGF are least effective in modulating Aâ aggregation and cytotoxicity. Therefore, the two additional methyl groups of BBG and other structural differences between the congeners are important in the interaction of BBG with Aâ leading to formation of nontoxic Aâ aggregates. Our findings support the hypothesis that generating nontoxic aggregates using small molecule modulators is an effective strategy for reducing Aâ cytotoxicity. Furthermore, key structural features of BBG identified through structure-function studies can open new avenues into therapeutic design for combating AD.
Amyloid beta-Peptides Benzothiazoles