Alzheimer’s disease (AD) is associated with amyloid formation and accumulation in the brain contributing to neurodegeneration. To date, there are no suitable mitigation strategies that stop or slow AD progression. Novel therapeutic approaches applicable at different stages of AD amyloid formation are direly needed. The long-term goal of this research is to establish effective treatment strategy for AD. Our overall objective is to develop and validate a new proprietary class of anti-amyloidogenic molecules to impede the formation of Aβ toxic oligomers. The specific aims of our research are 1) to provide a relevant library of small molecules, 2) to identify the key chemical moieties driving their effect in interfering with oligomer formation (structure-activity relationship). The potency of at least three different series of small molecules to reduce the formation of amyloid fibrils and toxic oligomers was assessed in vitro using biophysical methods such as Thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM). Based on the screening of 30 newly synthesized molecules, we discovered KN-21-48 and MO-19-49 as amyloid inhibitors of Aβ1-40. A preliminary structure-activity relationship study indicates that compounds KN-21-48 and MO-19-49 can serve as a scaffold for further modifications in the design of more potent novel small molecules targeting amyloidogenesis in AD. This project may lead to a better understanding of AD by providing a model compound that may confirm or deny the role of amyloidosis in disease progression.
