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).