Rational Design of Single Chain Domain Antibodies to Human Tau Aggregates

The aggregation of tau plays a key role in the development of Alzheimer's disease and a range of other neurodegenerative diseases, including progressive supranuclear palsy and Pick's disease. The aim of this project is to design single chain domain antibodies to different epitopes of human tau to enable the imaging and detection of tau aggregates in cells, tissue and biofluids, and as potential inhibitors of tau aggregation. Initial testing will be computational and once the best candidates have been found these will then be expressed in bacteria and purified. They will then be tested to determine their binding affinity for monomeric and aggregated tau to find antibodies that have high affinity and specificity for different forms of tau aggregates and are sensitive or insensitive to common post-translational modifications. The best antibodies will then be labelled with dyes for sensitive imaging of tau aggregates in cell models of neurodegenerative disease and used to pull-down and enrich tau aggregates in human biofluids such as CSF to explore if the number of aggregates changes during disease progression. The antibodies will also be tested in vitro as inhibitors of tau aggregation and the best inhibitors will be used in a cell seeding model to see if they are effective at inhibiting spreading of tau aggregates from cell to cell.