Diseases such as Alzheimer’s disease (AD) are progressive and appear to involve brain networks. We have proposed that pathological tau assemblies, which underlie dementia in AD, move from cell to cell to cause pathology to spread through the brain. The mechanism by which tau binds the cell surface to enter and corrupt normal tau on the inside could be an important place to block the disease. We have worked on this question for approximately 10 years and have identified the “receptor” to which tau binds on the cell surface, as well as critical cellular enzymes required to modify this receptor so that it can bind tau. In the first component of this work, we will test in animal models whether reduction of a specific enzyme, NDST1, which is critical to modify the surface receptor, will prevent cells from developing tau pathology. If this line of work is successful, it immediately will suggest important new drug development strategies. The second line of work will determine how pathological tau directly translocates across the plasma membrane. This process, which is implied strongly by our prior work, breaks certain fundamental rules of biochemistry. Specifically, it is unclear how proteins such as tau, especially in large assemblies, could cross the lipid bilayer that makes up the cell membrane. We will use advanced biochemical and imaging approaches to confirm this mechanism and identify factors that play a fundamental role.