Neurodegenerative diseases are the greatest unmet medical problem of our time and are predicted to exert an enormous health burden by the mid-21st century. Almost all neurodegenerative diseases are characterised by the accumulation of intracellular protein aggregates inside cells of the brain. This leads to deterioration of cellular function, cell death and inflammation in the brain, ultimately leading to a progressive deterioration in brain health.
One protein with this tendency, tau, forms filaments in some of the most common neurodegenerative diseases including Alzheimer’s disease, as well as in rarer diseases collectively called tauopathies. As repetitive and dense protein structures, tau filaments are hard for cells to destroy by its usual mechanisms.
Our lab asks whether intrinsic immunity, the natural ability of cells to destroy conventional pathogens like viruses, can be repurposed towards aggregated proteins. We demonstrated in 2023 that an intracellular antibody receptor, TRIM21, can be used to evoke a potent response against tau. We are building on these observations to develop an understanding of how the cells of the brain can be directed to degrade tau filaments. We have numerous ongoing projects which broadly fall into the following areas.
Immunotherapy
It is not yet clear how antibodies, which are largely present outside of cells, can promote clearance of tau, which mostly resides inside cells. Following our discovery of a critical role of TRIM21 in immunotherapy, we are using antibody engineering and gene therapy approaches to seek new methods for targeting intracellular protein aggregates. By exploiting the requirement of TRIM21 to multimerise, we have devised methods that are selective for aggregated forms of the targets.
Tau patho-biology
Tau aggregates have conformations that are specific to individual diseases: for instance, tau in Alzheimer’s diseases misfolds in a shape distinct to that in progressive supranuclear palsy or corticobasal degeneration. Understanding the relationship between tau filament shape and its pathogenesis is therefore critical to a global understanding of disease. We are developing new methods to allow tau conformations from disease to be studied in the lab. We study important aspects of how tau enters cells, retains propagated biological characteristics and behaves in complex cellular models.
Innate immune interactions
The brain of Alzheimer’s patients is in a chronically inflamed state, somewhat similar to how the body responds to infection. While this type of inflammation may help clear up dead cells and aggregated proteins, is likely that this inflammation is damaging over the long term. We are interested in a signalling molecule called interferon which is present in the Alzheimer’s brain. In the context of virus infection interferon helps prevent ongoing infections. We have found however, that interferon makes tau pathology worse in animal and cellular models and are undertaking further work to understand this effect.
Collaboration
We work within academia and with industrial partners to develop target-directed and unbiased drug discovery programmes in these areas.
McEwan Lab 