Multi-targets drug against Alzheimer (AD) disease: Mechanistic studies of drug action through amyloid and associated signalling pathways.

Project Description

The aim of this project is to synthesise a small discrete library of novel compounds based on our lead compound, by applying the methodology developed in our laboratory, and to study the mechanism of action of active one and confirm the multi target directed hypothesis. The synthesis of compounds will be carried out using the chemistry we have developed.Full characterisation of the compunds will be carried out using NMR and Mass spectrometry. The synthesised compounds will be screened with our panel of antioxidant assays (DPPH, FRAP and ORAC). Their ability to inhibit β-amyloid aggregation and acetyl choline esterase enzyme will be determined using Thioflavin and Ellman’s assays respectively. The inhibition of MAO (involves in ROS production) and BACE-1 (cleaves amyloid precursor protein during the production of amyloid peptides) enzymes will also be determined using commercial kits. Based on the latter results, the most active compound will be further studied with neuron and microglial cell models. It has been accepted that oxidative stress and neuroinflammation play important roles in the pathology of AD. There is a close association among oxidative stress, neuroinflammation, and Aβ generation. Aβ aggregation causes microglial activation, leading to production and secretion of multiple pro-inflammatory cytokines. The ability of the selected compound to protect neurons from oxidative damage will studied using routine cell viability assay. Using microglia cells the ability of our selected compound to reduce oxidant stress and inflammation by modulating signalling pathways such as Nrf2/HO-1, NF-κB, MAPK will be carried out using established commercial kits.

Altogether, the results from this project will validate our multi targets strategy and the confirm their main targets and mechanism of action. This will transform the way complex disease can be treated in the future.