Designing novel therapeutics for Alzheimer’s disease using structural studies of tau

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is a condition of aging, primarily afflicting adults 65 and older, and is the most common cause of dementia worldwide. The histopathological hallmarks of AD are amyloid plaques and neurofibrillary tangles (NFTs), formed by aggregation of proteins amyloid-β and tau, respectively. Studies have shown NFT formation is correlated with brain atrophy and cognitive decline. Therefore, halting tau aggregation at early stages to prevent disease progression is a potential therapeutic avenue for AD. Previous studies in our group determined the micro-electron diffraction structure of 305SVQIVY310, an aggregation-prone segment of tau. We designed a peptide-based inhibitor to target its aggregating interfaces, referred to as WIW, which has been demonstrated to halt tau aggregation in vitro and in cell models. To transport WIW across the blood-brain barrier (BBB), I have linked WIW to a peptide tag that enters the brain via receptor-mediated endocytosis by binding to low-density lipoprotein receptor-related protein 1. In Aim 1, I will probe the mechanism of action of WIW by solving a co-crystal structure of WIW with its target peptide, SVQIVY. In Aim 2, I will modify WIW to optimize its CNS delivery and plasma stability. In Aim 3, I will determine whether WIW or an optimized analog can inhibit tau aggregation in PS19 mice, a mouse model of tauopathy. Although WIW has been demonstrated to halt tau aggregation in vitro and in cell models, these proposed investigations will be the first structural characterization of the mechanism of action of WIW and the first characterization of its ability to halt tau aggregation in vivo.