Neurofibrillary tangles (NFT) is a pathological hallmark of Alzheimer’s disease (AD). NFT is composed of aggregated tau protein and is correlated to cognitive decline in dementia progression. NFT spreads in the brain in a prion-like manner, mediated by the interaction between tau and neuronal surface glycans. The long-term goal is to study the structural details of tau-glycan interaction and to discover drugs to disrupt this interaction for disease-modifying treatment of AD. In this proposal, we will study the tau-heparan sulfate interaction from at the molecular (aim 1), the cellular (aim 2), and organismal level and carry out drug discovery (aim 3).

Alzheimer’s disease (AD) is one of the most serious challenges to public health in US. Tau protein aggregates to form neurofibrillary tangle (NFT), a pathological hallmark of AD. NFT spreads transcellularly via the interaction between tau and cell surface glycans. We will study the structural details of tau-glycan interaction for structure-based drug discovery. The detailed data on the interaction between tau and glycan will provide tremendous insight into molecular mechanism of tau pathology and AD pathogenesis, and point to new directions in AD drug discovery.