A new study published in Nature reports the structure of tau using a magnified look at filaments in a patient with Alzheimer’s and explores what this might mean for the treatment of Alzheimer’s disease.
Dr Rosa Sancho, Head of Research, Alzheimer’s Research UK, said:
“A buildup of tau protein is a feature of a number of different degenerative brain diseases, and this work could help to answer key questions about why it starts to behave unusually and how it leads to such a wide variety of conditions. As well as improving our understanding of diseases like Alzheimer’s, knowing the precise structure of tau will help inform research into new treatments. Drugs that could clear away clumps of protein in the brain are a key goal for researchers, but to directly affect these proteins, molecules that make up a drug need to latch on and bind to their surface. Knowing the precise shape of these complex protein structures is enormously valuable in guiding the development of targeted drugs.
“Technological advances combined with the ingenuity of researchers like this team in Cambridge, are constantly pushing back the frontiers of our understanding of the diseases that cause dementia. The findings in this study represent an important step forward in the way we can study and understand proteins that are thought to be among the chief culprits in diseases like Alzheimer’s.”
Prof. David Allsop, Professor of Neuroscience, Lancaster, said:
“There are two main characteristic changes that occur in the brains of people with Alzheimer’s disease. These are the senile plaques, which are found outside of nerve cells, and the neurofibrillary tangles, found inside nerve cells. Much of the research effort to find new drugs to treat this disease has focused on the senile plaques, but so far these drugs have all failed in late-stage clinical trials. This has led to a change in direction in recent years, and the tangles are now receiving more attention as a possible drug target.
“Fitzpatrick and colleagues have paved the way for development of new drugs designed to prevent tangle formation by deciphering the molecular structure of the ‘tau’ protein filaments that make up the tangles at atomic resolution. The molecular models arising from their work can be used to design new drugs that interact with critical regions on the tau molecule to prevent its assembly into tangles.
“However, there are some formidable obstacles to be overcome for this approach to be successful. Any tangle-acting drug must cross the blood-brain barrier to enter the brain, and must also penetrate inside nerve cells in affected brain regions. The other main problem is that tau protein has a very important function in these nerve cells. It is involved in the assembly of structures called ‘microtubules’ that transport materials along the ‘axons’ of nerve cells, and interfering with this process would be highly problematic.
“We are a long way from having an effective tau-directed drug, but the work of Fitzpatrick and colleagues is at least a step in the right direction.”
Dr Tara Spires-Jones, Interim Director, Centre for Cognitive and Neural Systems, University of Edinburgh, said:
“This study in Nature shows for the first time the detailed structure of tau fibrils from the brain of an Alzheimer’s patient. Tau protein normally helps brain cells function, but in Alzheimer’s disease, tau clumps up in ‘tangles’ inside the cells. These tangles spread through the brain as the symptoms of disease progress. Understanding the changes in tau that happen in patient brains was not previously possible in this much detail. This study using cry-electron microscopy on tau from an Alzheimer patient’s brain substantially advances what we know. These results will be useful for developing molecules to detect tau tangles in patients and potentially for developing treatments. The technique will be useful to study other diseases.”
Prof. John Hardy, Professor of Neuroscience, UCL, said:
“This is a fantastic piece of work which will help us understand the pathogenesis of Alzheimer’s better. It really is a tour de force.”
Dr James Pickett, Head of Research at Alzheimer’s Society, said:
“Tau protein, one of the hallmarks of Alzheimer’s disease, has never been seen in this level of detail before. Many drugs work like a key in a lock, and this discovery shows us the inner workings of the tau protein ‘lock’.
“The ability to picture what the lock looks like could help scientists design more precise drugs that act on the tau protein and stop damage to the brain. With this knowledge, computer models can measure millions of potential drug molecules against the tau protein, giving immediate clues to suggest which should be tested further.
“Developing these accurate pictures is technically very challenging. The picture presented comes from studying the tau protein in a single person’s brain who died with Alzheimer’s disease. But one third of people with dementia have a disease other than Alzheimer’s, so studying the shape of tau in other forms of dementia will be important to help discover drugs for those conditions.
“This study could take us into a new era of drug design, but it can take 10-15 years to develop new drugs from this very early stage of drug discovery. There is currently no cure, but studies like this give us hope that research will deliver better treatments for people with Alzheimer’s disease.”
* ‘Cryo-EM structures of tau filaments from Alzheimer’s disease’ by Fitzpatrick et al. published in Nature on Wednesday 5th July.
Prof. Allsop: “None to declare.”
Dr Spires-Jones: “I am employed by the University of Edinburgh and am a member of the Grant Review Board for Alzheimer’s Research UK.”
Prof. Hardy: “I consult for Ceracuity Pharma”
Dr Pickett: “There are no interests to declare.”