Uncovering the Molecular Mechanisms of Selected Drug Candidates Derived from Systematic Alzheimer’s Drug Repositioning

2020

In fiscal year 2020, we focused on identifying molecular mechanisms related to six confirmed screening hits and predicting more candidates based on such mechanisms. Specifically, our collaborators in the Tanzi lab and the Kim lab successfully confirmed six primary hits through secondary screening and toxicity tests, and we were able to identify significantly changed pathways potentially related to the p-tau clearance ability of each hit. We were able to carry out in-depth pathway analysis for these six confirmed cases and identified four subclusters potentially bearing different mechanisms of p-tau clearance. One of the subclusters was used as bait in our in silico predictions and generated 33 candidates, three of which were validated previously in the Alzheimer’s in a Dish model as being able to clear p-tau. Next year, we will continue working on validating the predictions in this list of 33 candidates, and also perform additional in silico predictions from other confirmed hits. We also will generate single cell RNA-seq data to study the effect of three to five confirmed hits on different cell types within the Alzheimer’s in a Dish model. This analysis will facilitate the effort to understand how different types of cells in the brain microenvironment talk to each other, and how such communications are altered in the AD brain. Ultimately, such in-depth and systematic understanding on neuronal-glial crosstalk will open the door for novel therapeutics.


Funding to Date

$200,000

Focus

Drug Discovery, Genes to Therapies™

Researchers

Stephen T.C. Wong, Ph.D.