Winner of Brain Prize 2018, Prof Michel Goedert, on our best hope for tackling Alzheimer's disease
Programme leader at MRC Laboratory of Molecular Biology in Cambridge says we could one day be screened and treated before it develops
‘If this goes on, with an ageing population, there will be more and more cases and, even just financially, it will be a disaster for health services across the world.”
It is a sobering thought from Professor Michel Goedert, who has been studying Alzheimer’s and other neurodegenerative diseases for decades.
More than half a million people in the UK and about 10 million across Europe have Alzheimer’s, making it the most common type of dementia. Age is the biggest risk factor – Alzheimer’s primarily affects those over 65 and your chances of developing it approximately double every five years. One in six over the age of 80 have the disease.
Prof Goedert, a programme leader at the MRC Laboratory Molecular Biology in Cambridge since 1987, believes our best hope of fighting this awful condition lies in learning to predict who will get it and preventing it from developing in the first place.
His work has just earned him – along with three other neuroscientists – the Brain Prize for 2018 from the Lundbeck Foundation in Denmark. Worth one million euros, it is the most valuable award there is for brain research.
Prof Goedert – who described the award as “quite unexpected” – won the prize for ground-breaking work dating back to the 1980s that was initiated at the LMB by Aaron Klug and Martin Roth and initially involved Claude Wischik, Tony Crowther, Michal Novak, John Walker, Cesar Milstein, Ross Jakes and Maria Grazia Spillantini.
Using human brain tissues, transgenic mice, cultured cells and purified proteins, Prof Goedert demonstrated – despite considerable initial scepticism – the importance of tau protein in Alzheimer’s disease.
“The brains of people who have died of Alzheimer’s disease have two abnormalities – so-called plaques and tangles. These are protein aggregates,” he explains.
Ultimately, these abnormalities lead to the death of nerve cells and the loss of brain tissue.
Plaques are caused by the clumping together of beta-amyloid protein pieces outside nerve cells, which block cell-to-cell signalling.
Tangles, meanwhile, are inside the nerve cells and occur when tau protein assembles into clusters of filaments and becomes insoluble. These are the focus of Prof Goedert’s work.
“We all have tau proteins in the brain. Its function is probably to stabilise microtubules inside cells,” he says.
Microtubules are a cellular transport system, like rails, that help material to move in our bodies.
“But it is not a loss of function disease,” Prof Goedert stressed. “It’s a gain of toxic function. The tau protein is one of many proteins that can stabilise these microtubules.
“It looks like if a portion of it turns into these abnormal structures, it’s not sufficient to disrupt this process. The formation of these inclusions is what causes the disease of the cell.”
A pathological pathway leads from the soluble to insoluble filamentous tau.
“Somewhere along it lies the cause of the disease, in the sense of why the nerve cells degenerate and die, which leads to the symptoms of the disease,” explains Prof Goedert.
“Everybody would agree that something on this pathway causes this. Some would argue that there are aggregate species – not the final filaments, but smaller – that have a very active toxic effect.
“I would think it’s equally likely that if you have loads of these filaments inside cells, over a long period of time they are like space-occupying lesions inside a cell body and particularly inside very fine processes.
“They would disrupt all sorts of things inside the cells, including the transport of materials to the periphery, and then at the end the cell dies.
“In the past 10 years, we’ve also found tau proteins exhibit prion-like properties – they can fold in ways that can be transmitted to soluble tau molecules.”
Prions are the misfolded protein equivalent of viral infections and enable a neurodegenerative disease to spread. In the case of Alzheimer’s, it means the tau protein aggregates gradually take over.
“These aggregates form in a small region of the brain and over a long period of time spread to the brain as a whole, and then symptoms appear. Initially, when you have small numbers of these aggregates, there are no symptoms,” adds Prof Goedert.
Much of the group’s work now is focused on the mechanisms behind the spread.
“If we understand more, we might be in a position to prevent the spread from happening and develop compounds that can prevent the symptoms. In addition, you need to be able to predict who is going to get the disease.
“These very early aggregates that form, before the spread occurs, are probably present in people’s brains for decades before the symptoms appear. If you could detect those and predict at an individual level for example that if a person lives another 20 years they are going to get the disease, then you would be in a position to treat that person and prevent the symptoms,” says Prof Goedert, who is an honorary professor of experimental molecular neurology at the University of Cambridge.
“You could give the compounds to everyone over the age of 50. But every treatment has some sort of side effect. Then you would have to treat people who are perfectly healthy.”
No compounds yet exist to deal with the aggregation of tau proteins. And those that have been trialled to tackle amyloid plaques have so far failed.
“One possibility is that the compounds were perfectly good but were given too late,” suggests Prof Goedert. “I think identifying people at risk of developing the disease at a point when they have no symptoms but have some of these pathologies in the brain is really crucial. These are the biomarkers. But until recently it was not possible to detect these things inside living people.”
Studies of the brains of thousands of people have shown that the vast majority have small numbers of these aggregates. Those who had Alzheimer’s had many more of them. Others were in between.
“When you see small numbers of aggregates in the brain, you extrapolate that had the person lived for another 20-30 years, they would have got the disease,” says Prof Goedert.
“More recently, it’s become possible to identify aggregates in the brains of living people using PET (positron emission tomography) scanning. You inject mildly radioactive compounds that bind specifically to the aggregates – they don’t see the protein where it’s not aggregated. Then using imaging techniques, you can detect the aggregates.”
PET scans can now be used to detect both beta-amyloid plaques and aggregated tau protein, although the test is not yet sophisticated enough.
“It’s still very early but I think this is going to revolutionise everything,” says Prof Goedert. “In principle you could take a person and image them every year and see whether the pathology progresses. The problem is resolution. Are you going to detect very small numbers of these things? Over time that will improve – but at the moment it’s not there.
“In the long run, it could be like breast cancer screening for women or colonoscopies for men and women. You would take people at the age of 50 and have a PET scan every five or 10 years.”
Current therapies – cholinesterase inhibitors and glutamate receptor antagonists – treat some of the symptoms of Alzheimer’s, but do not tackle the underlying biological causes.
These symptoms often begin with memory lapses and gradually progress through to problems with communication, reasoning and orientation. In the latter stages, patients may have difficulties eating or walking, and become increasingly frail and needing help with all aspects of daily life.
“There are so many people working on it now, one can be reasonably optimistic in terms of the timeframe. It’s reasonably clear now what one has to do,” says Prof Goedert.
Understanding the mechanisms of the disease is key – and the work of Prof Goedert and those he shared the prize with is likely to play a critical role in future treatments.
Most recently, Prof Goedert has been examining the structure of the tau filaments.
“This lab is very famous for its cryo-electron microscopy technique, which Richard Henderson got a Nobel Prize for last year, and we are collaborating with the group of Sjors Scheres to look at high resolution structures of these tau filaments for Alzheimer’s disease. That was published last year. We’re now doing it for Pick’s disease and other diseases – that’s not published yet.
“It tells you how similar or different they are, which I think has a bearing on the prion-like properties of these aggregates. They are clinically-different diseases,” he says.
Different tau filaments feature in the distinct neurodegenerative diseases such as Pick’s disease and progressive supranuclear palsy, where they form in the absence of beta-amyloid deposits outside brain cells.
Prof Goedert’s recent work in mouse models and in cell cultures suggests filamentous tau clusters propagate through self-seeding.
“Experimentally, they do. There is evidence from the human brain that is consistent with that. But proving the mechanism takes place in the human brain is difficult. You would have to interfere with the process and block it to show that,” he said. “In the long run, prevention is the thing to do.”
With his decades of work helping us, bit by bit, to understand the scourge of Alzheimer’s, that may one day be possible.
The brains behind the prize
Prof Michel Goedert shares the 2018 Brain Prize with Bart De Strooper (London and Leuven), Christian Haass (Munich) and John Hardy (London) for their groundbreaking research on the genetic and molecular basis of Alzheimer’s disease.
Although he knows them all, Prof Goedert has not collaborated with the others because they all work primarily on beta amyloid plaques.
Professor Bart De Strooper, the director of the UK Dementia Research Institute at University College London, and professor of molecular medicine at KU Leuven and VIB, Belgium, discovered that presenilin is a protein that ‘cuts’ other proteins into smaller pieces – an important and complex process in normal cell signalling. Mutations in presenilin genes lead to the production of abnormal amyloid, the main constituent of the plaques in the brains of Alzheimer’s patients.
Professor Christian Haass, at the Ludwig Maximilian University of Munich and at the German Centre for Neurodegenerative Disorders, said: “My research into Alzheimer’s has focused on the cascade of events starting with amyloid and progressing through the development of plaques and tangles that eventually kill brain cells and destroy memory.”
His pivotal finding was that amyloid production was in fact normal and not necessarily part of a pathological process, while more recently he has explored inflammation in neurodegenerative disorders, which he suggests may at least initially play a protective role.
Professor John Hardy, chair of molecular biology of neurological disease at the Institute of Neurology, University College London, found mutations in the gene for the protein amyloid in a family with early onset disease. He proposed a ground-breaking ‘amyloid hypothesis’ for Alzheimer’s, suggesting that the disease was initiated by the build-up of this protein in the brain. The disease progresses when there is an imbalance in the production and the clearance of amyloid.
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