The molecular mechanism of progression of neurodegenerative diseases caused by aggregation of the tau protein is not understood. According to a model of prion pathogenesis, once a tau assembly forms in one cell, it can escape that cell and move to an adjacent cell, where it is taken up. Prior to uptake, the tau assembly must bind specialized surface proteins. After binding, the tau enters vesicles within the second cell. However, it is unknown how tau might escape a vesicle to enter the cytosol and serve as a template for its own replication. We have determined that after binding appropriate surface proteins, tau assemblies—even those that are very large—can directly cross the plasma membrane to enter the cell. This presents a fascinating biophysical problem since the lipid bilayer of a cell membrane is not thought to be permeable to large protein complexes. Through the study of these molecular mechanisms, we hope to gain insight into why Alzheimer’s and related disorders are relentlessly progressive, and also to identify new targets to block this process.
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 the 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.