(157e) Structure-Function Analysis of the Novel Small Molecule Modulators of Amyloid-Beta Aggregation and Cytotoxicity

Alzheimer’s disease (AD) is a debilitating and ultimately fatal disease. Currently, 5.3 million people are affected in the U.S., with the number projected to rise to 13.5 million by 2050. A hallmark of AD is the accumulation of neurotoxic amyloid-beta peptide aggregates. Growing evidence suggests that soluble amyloid-beta oligomers are the primary toxic pathological species whose presence strongly correlates with dementia. Therefore, logically, a promising therapeutic strategy to inhibit disease progression is the reduction of neurotoxic amyloid-beta oligomers. To this end, numerous small molecules have been investigated for their potential to reduce and control the physiological concentrations of neurotoxic amyloid-beta species in the brain. However, the discovery and design of effective drug molecules has been hindered by both practical limitations, such as the low blood-brain-barrier permeability and intrinsic toxicity of small-molecules, and to limited understanding of their biophysical and biochemical functionality. Recently, we discovered that several small molecules with the demonstrated safety profiles significantly modulate amyloid-beta aggregation and reduce amyloid-beta-associated neurotoxicity. The small molecules identified were shown to bind to the specific sequence of amyloid-beta reducing cytotoxicity by generating non-toxic oligomers or promoting fibril formation. We have also identified critical structural features of the small molecules for their modulating capabilities on amyloid-beta aggregation and cytotoxicity through structure-function studies, which is expected to open new avenues into rational drug design for combating AD.