Junmei Wang (Associate Professor, Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh)
The formation of insoluble extracellular amyloid plaques and intraneuronal neurofibrillary tangles (NFTs), final products of the corresponding amyloid-β (Aβ) and tau aggregation processes, is the hallmark of a brain with Alzheimer’s disease (AD). Recently, soluble small oligomers of Aβ peptides and tau protein, the products in the early phase of aggregation, are found to be the most toxic in AD neuropathology. However, it is challenging to experimentally obtain detailed structural and dynamic information on the tau oligomerization process, a prerequisite to achieve rational drug design. In contrast, the state-of-the-art molecular dynamics (MD) simulations can provide atomistic details of the oligomerization process. We have developed a set of computational tools /protocols/models allowing us to identify potential inhibitors which can efficiently and effectively interfere with amyloid oligomerization. The in-silico prediction has been confirmed by in vitro assays. Moreover, this study also elucidates the molecular mechanism of amyloid- and tau oligomerization.