Developing Novel Molecules to Prevent Amyloid-Beta Aggregation

Alzheimer’s Disease (AD) affects and estimated 700,000 Canadians, a figure projected to grow to 1.7 million by 2050. Current treatment options are limited and there is no cure for the disease. One of the prevailing explanations for the cause of AD is the amyloid hypothesis, which posits that aggregates of amyloid-beta (Aβ) are the initiating pathological agents. Aβ self-assembles in the brain of AD patients, and these aggregates cause neuronal damage through several routes, including oxidative stress, membrane dysfunction, and causing synaptic dysfunction. Small molecules capable of inhibiting or modulating the formation of Aβ aggregates are therefore valuable both as potential therapeutics and as tools for understanding disease progression.

This project involves designing and evaluating novel phenylacetylene derivatives as inhibitors of Aβ aggregation. A novel compound library was designed using molecular docking with Aβ aggregate models, then synthesized using a two-step procedure: a Sonogashira coupling between an aryl bromide and trimethylsilylacetylene, followed by a base-catalyzed deprotection. Products were then characterized using ¹H NMR, ¹³C NMR, and LCMS to confirm purity.

The ability of these phenylacetylenes to prevent Aβ aggregation was assessed using a fluorescence-based kinetics assay. Aggregate morphology in the presence of promising inhibitors was assessed using transmission electron microscopy (TEM). The safety profile of the phenylacetylenes was tested in mouse hippocampal (HT 22) neuronal cells. Future work will further test their ability to rescue neuronal cells from Aβ-mediated cytotoxicity.

The data collected in this project will be used to develop a structure activity relationship (SAR) for phenylacetylenes to determine their potency in inhibiting Aβ aggregation. This work will contribute to both the development of potent small-molecule Aβ aggregation inhibitors, and to help understand the role Aβ aggregates play in Alzheimer’s disease.