The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Florida, United States
Alzheimer disease (AD) is one of the most debilitating and progressive neurological disorders we are facing as a society. The key pathological hallmarks of AD are the extra neuronal plaques containing fibrillar amyloid-β (Aβ), and the neurofibrillary tangles inside neurons that are composed of hyperphosphorylated tau protein (p-tau). To date, the majority of AD drugs target Aβ production or the clearance because they were originally thought as the valid targets in the development of the disease but unfortunately, most of the clinical trials are failing. The two most recent anti-Aβ monoclonal antibody therapeutics approved by the FDA have minimal benefits and may cause significant and severe side effects. Thus, there is an urgent need to develop AD therapeutics outside the realm of Aβ. Small-molecule compounds that target the aggregation and toxicity of hyperphosphorylated tau are promising candidates because of the spatiotemporal distribution of the p-tau deposited in the brain correlates with the cognitive degeneration in patients of AD and other neurodegenerative tauopathies that do not have significant Aβ buildup. Hence, there is high interest in developing inhibitors of hyperphosphorylated tau aggregation due to their importance and pivotal role in Alzheimer’s disease. Here, we will be presenting the first high-throughput screen based on the aggregation and cytotoxicity of p-tau. We employed a fluorescence assay looking at p-tau aggregation that was developed in 96 well format and subsequently adapted in 1536 well format for high-throughput screening. This assay is based on the fluorescence of thioflavin (ThS) which changes upon binding to the amyloid structure of p-tau. A high-throughput screen of > 100,000 small molecules found several lead series of hits. Ultimately this study helps understand the molecular details of p-tau aggregation and toxicity which could provide a path to develop new efficacious therapeutics for the treatment of Alzheimer's disease and other neurodegenerative diseases.