Abstract
The aggregation of Afi42 is established as a key factor in the development of Alzheimer's disease (AD). Consequently, molecules that inhibit aggregation of peptide may lead to therapies to prevent or control AD. Several studies suggest that oligomeric intermediates present during aggregation may be more cytotoxic than fibrils themselves. In this work, we examine the inhibitory activity of an antibiotic MXF on aggregation (fibrils and oligomers) and disaggregation of Afi42 using various biophysical and microscopic studies. Computational analysis was done to offer mechanistic insight. The amyloid formation of Afi42 is suppressed by MXF, as demonstrated by the decrease in both the corresponding ThT fluorescence intensity and other biophysical techniques. The lag phase of amyloid formation doubled from 4.53 to 9.66 h in the presence of MXF. The addition of MXF at the completion of the fibrillation reaction, as monitored by ThT, led to a rapid, concentration dependent, exponential decrease in fluorescence signal that was consistent with loss of fibrils. We used TEM to directly demonstrate that MXF caused fibrils to disassemble. Our docking results show that MXF binds to both monomeric and fibrillar forms of Afi42 with significant affinities. We also observed breaking of fibrils in the presence of MXF through molecular dynamics simulation. These findings suggest that antibiotic MXF could be a promising lead compound with dual role as fibril/ oligomer inhibitor and disaggregase for further development as potential repurposed therapeutic against AD.