How Professor Giovanna Mallucci will lead Cambridge fight against dementia

PUBLISHED: 22:04 09 May 2017 | UPDATED: 10:51 20 May 2017

Amyloid plaques on axons of neurons affected by Alzheimer's disease

Amyloid plaques on axons of neurons affected by Alzheimer's disease

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An announcement that the University of Cambridge will help form the new £250million UK Dementia Research Institute came on a day that two promising drugs were named as potential treatments.

Doctors consult over an MRI scan of the brain.Doctors consult over an MRI scan of the brain.

Professor Giovanna Mallucci has the job of leading the new centre on Cambridge Biomedical Campus tasked with finding new ways to diagnose, treat, prevent and care for people with dementia.

The centre joins others at Cardiff University, the University of Edinburgh, Imperial College London and King’s College London in forming the new UK Dementia Research Institute (UK DRI), representing a concerted effort to tackle a group of diseases that affect millions around the world.

Prof Mallucci said: “The mission of the DRI overall is to take a transformative change in the understanding of the cellular mechanisms that make brain cells go wrong in dementia and degenerative brain disease and discovering new ways of treating based on those insights.

“In Cambridge we have such world-leading expertise in so many different fields so we are focusing on cross-disciplinary research, integrating chemistry and biophysics along with classic cell biologists such as myself who understand disease.It’s going to be a real dementia hub.

Prof Giovanna Mallucci, University of Cambridge, UK Dementia Research Institute, CambridgeProf Giovanna Mallucci, University of Cambridge, UK Dementia Research Institute, Cambridge

“There are lots of avenues but what you need is a couple of things that are going to change the course of disease and Cambridge is very well-positioned for those kind of discoveries. We have real momentum on some repurposed drugs.”

It is in this area that a team led by Prof Mallucci has made a potentially significant breakthrough.

Having identified a major pathway that leads to brain cell death in mice, the scientists have now found two drugs that block that pathway and prevent neurodegeneration, with minimal side effects in the rodents.

One of these drugs – trazodone hydrochloride – is already licensed for use in humans as an antidepressant.

1. Healthy neuron. 2. Neuron with amyloid plaques (yellow). 3. Dead neuron being digested by microglia cells (red)1. Healthy neuron. 2. Neuron with amyloid plaques (yellow). 3. Dead neuron being digested by microglia cells (red)

Prof Mallucci said: “The exciting development is that we’ve bypassed the whole drug discovery pipeline, which can take forever. You don’t know what’s going to work in humans but it means we don’t have to wait 20 years to find something.”

She added: “We know that trazodone is safe to use in humans, so a clinical trial is now possible to test whether the protective effects of the drug we see on brain cells in mice with neurodegeneration also applies to people in the early stages of Alzheimer’s disease and other dementias. We could know in 2-3 years whether this approach can slow down disease progression, which would be a very exciting first step in treating these disorders.

“Interestingly, trazodone has been used to treat the symptoms of patients in later stages of dementia, so we know it is safe for this group. We now need to find out whether giving the drug to patients at an early stage could help arrest or slow down the disease through its effects on this pathway.”

It is known that misfolded proteins build up in the brains of those with neurodegenerative diseases and are a major factor in dementias such as Alzheimer’s and Parkinson’s as well as prion disease.

An MRI scanAn MRI scan

The team led by Prof Mallucci at the Medical Research Council’s (MRC) Toxicology Unit in Leicester originally discovered that this accumulation of misfolded proteins in mice with prion disease over-activated a natural defence mechanism, ‘switching off’ the vital production of new proteins in brain cells.

Switching protein production back on with an experimental drug halted neurodegeneration but the drug tested was toxic to the pancreas and not suitable for testing in humans.

But in a study published in Brain, the researchers revealed how they identified a number of suitable candidates after testing 1,040 compounds from the National Institute for Neurological Disorders and Stroke, initially in worms, which have a functioning nervous system.

Testing on mice with prion disease and a form of familial tauopathy or frontotemporal dementia (FTD) identified two drugs that restored protein production rate.

Old man suffering from Alzheimer's Disease. Alzheimer's disease is the most common cause of dementia. Worldwide, nearly 44 million people have Alzheimers or a related dementiaOld man suffering from Alzheimer's Disease. Alzheimer's disease is the most common cause of dementia. Worldwide, nearly 44 million people have Alzheimers or a related dementia

Both trazodone hydrochloride and dibenzoylmethane, a compound being trialled as an anti-cancer drug, prevented the emergence of signs of brain cell damage in most of the prion-diseased mice and restored memory in the FTD mice. In both, the drugs reduced brain shrinkage – a feature of neurodegenerative disease.

“We think it may be quite broadly applicable but we’ll just have to see,” said Prof Mallucci. “The process it targets is activated in many diseases from Alzheimer’s to Parkinson’s to frontotemporal dementia but until you do the trials you don’t know what it means. In mice, you can see those pathways are involved in the disease process.”

The research was funded by the MRC and Prof Mallucci was funded by a grant from Alzheimer’s Society and Alzheimer’s Drug Discovery Foundation.

Dr Rob Buckle, chief science officer at the MRC, said: “This study builds on previous work by this team and is a great example of how really innovative discovery science can quite quickly translate into the possibility of real drugs to treat disease.”

The UK DRI will work on developing new treatments for Alzheimer'sThe UK DRI will work on developing new treatments for Alzheimer's

Dr Doug Brown, director of research and development at the Alzheimer’s Society, added: “We’re excited by the potential of these findings. They show that a treatment approach originally discovered in mice with prion disease might also work to prevent the death of brain cells in some forms of dementia. This research is at a very early stage and has not yet been tested in people - but as one of the drugs is already available as a treatment for depression, the time taken to get from the lab to the pharmacy could be dramatically reduced.”

It is this type of progress Prof Mallucci will hope for in her new role as one of the associate directors of the UK DRI. She will be joined in Cambridge by up to four leaders of foundation programmes. The centres have been awarded a total of 20 professorships and seven fellowships in the foundation phase and are now seeking talented researchers worldwide.

Professor Bart De Strooper, director of the UK DRI, said: “The shared vision between the centres will be at the heart of the DRI’s success, and this creativity at the borders will lead us to truly understand dementias and how they progress. We selected the centres based on innovative, excellent science, evidence of strong leadership, the alignment of goals with the DRI as a whole, and the ability to grow and collaborate as the institute gathers pace.

“An overarching theme from the University of Cambridge was the excellence of its science. Professor Mallucci’s energy and commitment to the cause was clear and I am confident she will drive successful interactions not only between her team’s programmes but with the wider DRI.”

Neurons in the brainNeurons in the brain

Intriguingly, although we often hear of a dementia timebomb amid ageing populations, research led by the University of Cambridge last year suggested the UK had seen a 20 per cent fall over the past two decades – primarily in men.

They concluded that while changing diagnostic methods and criteria were identifying more people as having dementia, improvements in health and education - including increased attention to diet and exercise – may be driving a reduction in dementia risk in some countries.

The researchers interviewed 7,500 people in Cambridgeshire, Newcastle and Nottingham between 1991 and 1994 with repeat interviews at two years to estimate incidence, before repeating the work with a new sample of people 20 years later. They found that in the UK there are just under 210,000 new cases per year – 74,000 in men and 135,000 in women – compared to an anticipated 250,000 new cases.

It was suggested a fall in smoking and improved vascular health might have been responsible for the reduction of cases in men.

Speaking at the time, Professor Carol Brayne, director of the Cambridge Institute of Public Health at Cambridge, said: “Our findings suggest that brain health is improving significantly in the UK across generations, particularly among men, but that deprivation is still putting people at a disadvantage. The UK in earlier eras has seen major societal investments into improving population health and this appears to be helping protect older people from dementia. Our evidence shows that the so-called dementia ‘tsunami’ is not an inevitability: we can help turn the tide if we take action now.”

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