Alzheimer’s and related neurodegenerative diseases are a major health problem. The tau protein is known to play a critical role in these disorders. In the disease state tau transitions from a normal, “healthy” three- dimensional shape to one that is capable of self-assembling into pathological aggregates. Remarkably, these aggregates, once formed in a brain cell, appear to exit that cell and gain entry into neighboring or connected cells, where they can serve as disease-causing “templates” to corrupt normal tau protein to an abnormal conformation. Free tau aggregates can bind the cell surface by interacting with specific proteins called heparan sulfate proteoglycans (HSPGs), which are modified in the cell through the attachment of sugar molecules, which themselves are modified by the addition of sulfate groups. These modifications occur during the synthesis of HSPGs, and depend on specific cellular enzymes. One enzyme, NDST1, was previously identified as being very important for enabling HSPGs to be properly modified so as to bind tau protein. Once bound to HSPGs, tau assemblies get into the cell, where they create more aggregates. The mechanisms by which tau can cross the cell membrane are unknown. It is also unknown whether the mechanisms that apply to tau are similar to those that function for other disease-causing proteins. This grant will test the role of NDST isoforms in a mouse model of tau-induced neurodegeneration to see if the pathway implicated by prior studies might be targeted to create new drugs for Alzheimer’s. Additionally, the grant will determine how tau assemblies can cross the cell membrane, and whether mechanisms that apply to tau also apply to other disease-causing proteins.