How do antibodies prevent tau pathology in Alzheimer’s disease?
Project ID: NMH17
Department: Department of Clinical Neurosciences
Supervisor: Dr. William McEwan
Second Supervisor:Prof. Maria Grazia Spillantini
Second Supervisor DepartmentDepartment of Clinical Neurosciences
Web page: https://mcewan-lab.com/
Dementia, including Alzheimer’s disease, affects 43 million people worldwide and is predicted to afflict 1 in 3 people born in the UK in 2015. There is currently no disease-modifying treatment. Pathology in several neurodegenerative diseases, including Alzheimer’s disease, is thought to be driven by the progressive aggregation of the protein tau. Ongoing work across industry and academia is generating therapeutic anti-tau antibodies that protect against tau aggregation in cell-based and in vivo models. Some such antibodies are currently entering clinical trials and are considered one of the most promising therapeutic avenues. However it is unknown how these antibodies exert their protective effects against tau pathology. It is therefore hard to predict which antibodies are likely to be most effective and hard to rationally engineer the antibodies for optimal efficacy.
The cell cytoplasm is protected by a dedicated receptor for antibody called TRIM21. This protein elicits the rapid destruction of antibody-antigen complexes whenever they occur in the cytosol. As antibodies are normally prevented from entering the cell by the plasma membrane, entry of antibodies to the cytosol is thought to only occur during pathological events that disrupt cell membrane integrity, such as viral infection. The aggregation of tau in Alzheimer's disease is thought to occur through a virus-like 'seeding' process whereby small quantities of aggregated tau are taken up by naive neurons where they promote the conversion of native tau to the aggregated conformation. Recent work shows that, like viruses, assemblies of tau can import antibodies with them when they enter the cell. This stimulates TRIM21 to initiate a very powerful destruction event that prevents seeded tau aggregation.
In this project, we will collaborate with R&D scientists within the AstraZeneca Neuroscience programme. The candidate will use state-of-the-art assays for the detection of tau pathology and help in the development of new models of tau spread in human stem cell-derived neuronal cultures. AZ will produce antibodies engineered such that interactions with important receptors, including TRIM21, are predicted to be altered. We will use these altered antibodies to investigate which antibody-receptor interactions are required for antibody-mediated protection. We will seek to use this information in the rational selection and engineering of antibodies as potential therapeutics in neurodegeneration.
The project will involve close collaboration between the group of Dr William McEwan and AstraZeneca’s Neuroscience division, currently based at Granta Park outside Cambridge though moving imminently to the Cambridge Biomedical Campus. Collaboration will involve regular meetings between the participants. Additionally, AZ will produce recombinant anti-tau antibodies, and their engineered derivatives, for use in determining the mechanisms of their protection. The student will spend time in the AZ Neuroscience labs utilizing appropriate in vitro bioassays. He or she will also spend time at AZ engineering antibody formats and gaining valuable experience in producing proteins such as tau for use in seeded aggregation assays. If appropriate this industrial placement has the potential to be upgraded to an iCASE studentship. The project will therefore combine cutting-edge hypothesis-driven academic research with the input from one of the leading industrial groups in the pursuit of therapies against Alzheimer's disease and other neurodegenerative disorders.