It’s been over a century since the discovery of Alzheimer’s disease, the most common form of dementia, and yet we are still without drugs that can slow or halt the condition that afflicts millions worldwide. While we have seen huge strides made in other major health challenges that face society, such as cancer, therapeutic solutions still remain elusive for dementia, which is now the leading cause of death in the UK. To pull apart the issue, we sat down with Professor Karen Duff to find out more about the obstacles facing the dementia field, her research into the fundamental biology behind the diseases, and where we go from here.
Exploring the where, the what and the tau
Professor Karen Duff joined the UK DRI’s hub at UCL as Centre Director in spring 2020 from Colombia University in the US. A world-leading expert in neurodegenerative diseases, her research focus is on the protein tau, which when accumulated into neurofibrillary tangles, is one of the main pathological hallmarks of the Alzheimer’s brain.
“Tau has an extremely important role to play in normal cell biology, with multiple functions including in the stability of neurones and the regulation of cognition,” says Professor Duff. “When the protein converts to an abnormal form, is found in an abnormal location or functions abnormally, it becomes a key feature of over 30 neurodegenerative diseases. In many conditions, tau is certainly the initiator, for example, in over half the cases of frontotemporal dementia. But in Alzheimer’s disease, it appears amyloid beta is the primary cause and tau’s effects are secondary. In either case, it certainly has a crucial role in the death of the neurones where the tau builds up in tangles. It’s clear that a neurone with abnormal tau will degenerate and I believe it has to be dealt with therapeutically.”
A significant obstacle to understanding the biology of neurodegenerative diseases has been in the generation of models that accurately recapitulate the pathology observed in human brains. Perhaps Professor Duff’s biggest achievement therefore has been in the development of an Alzheimer’s disease mouse model. Genetically engineered to establish tau pathology in the entorhinal cortex, the same brain region first affected in humans, the pathological protein sequentially spreads from neurone to neurone, region to region. The model enables significantly greater insights into disease processes. But why is deciphering the spread of protein so important to our understanding of disease?
Professor Duff explains: “A major change in the field has been in not just looking at the levels of the protein but where that protein is. In Alzheimer’s disease, the key moment in my mind is when tau spreads into the neocortex - then you get dementia. There is probably then very little you can do to rein it in. You may be able to slow it down, but you probably can’t stop the disease and so that’s the time window where we need to target therapeutics.”
Equipped with a range of models and techniques, Professor Duff’s lab at UCL is embarking on an exciting programme of research drilling down into the biological mechanisms behind tau propagation. Her aim is to determine the structure of spreading tau and which cell types are involved, which will be important in the development of much-needed treatments.