A UCL research team has found clues as to why some nerve cells die in dementia and not others, in a new study in fruit flies.
The Alzheimer's Research UK-funded study, published in Cell Reports, is helping to answer one of the biggest questions in dementia research, which is crucial to finding new treatments to slow or stop the condition from developing.
The researchers investigated why some nerve cells in fruit fly brains are resistant to disease processes that cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) in humans, while others are more vulnerable.
Lead author Dr Teresa Niccoli (UCL Institute of Healthy Ageing, UCL Biosciences) said: "In dementia, we see that some parts of the brain are affected and not others. For example, in FTD, it's nerve cells in the front of our brains - the part of our brain in charge of language processing, emotions and behaviour - that are affected first.
"But why are some nerve cells affected and not others? This is one of the biggest questions in dementia research.
"If we understand what makes some nerve cells resistant to diseases that cause dementia, then it might help us discover new treatments to stop these illnesses in their tracks."
What causes FTD and ALS?
ALS is the most common motor neuron disease, a group of conditions that progressively damage parts of the nervous system, and there is no known cure. ALS affects the brain and spinal cord by attacking the neurons and nerves which control movement, causing them to die and leading to progressive muscle weakness and sometimes dementia. There is currently only one approved drug for ALS in the UK, which extends lifespan by a few months, and is only effective for a tiny minority of patients. One third of patients die within one year of diagnosis.
FTD is a rare type of dementia that is related to ALS. Roughly 31,000 people in the UK live with FTD - less than one in every 1,000 people. FTD is a spectrum of conditions, with a range of complex biological mechanisms that can cause it. Symptoms can include difficulties with language and speech, but also changes in behaviour and personality, and can affect movement and muscle control. There is no cure for FTD, nor are there any treatments that can stop the condition from progressing.
Dr Niccoli is studying a population of tiny fruit flies with a mutation in the C9orf72 gene, which is the most common cause of both FTD and ALS.
People with changes in this gene tend to have a build-up of harmful protein clumps in nerve cells, eventually leading to FTD or ALS.
In a previous study, Dr Niccoli identified that changes in the C9orf72 gene caused the fly brains to process sugar differently.
Now, Dr Niccoli is using state-of-the-art technology to explore why some nerve cells in flies are more resistant to damage.
Understanding 'resilience' against genetic dementia disease
Dr Niccoli's latest study has revealed a key trait in fly nerve cells that are more resistant to the effects of the C9orf72 mutation.
She has found that nerve cells stand a better chance if they are better at clearing away harmful protein waste in flies with changes in the C9orf72 gene.
Dr Niccoli said: "Let's look at the fly brain like a city. The brain is a city made up of different 'neighbourhoods', with some disposing of their waste better than others.
"The neighbourhoods with good waste disposal measures, such as regular rubbish collection and efficient recycling systems, cope better when an unexpected event occurs - such as a flood or a chemical spillage - than neighbourhoods without these systems in place.
"When we looked at fly nerve cells with genetic changes linked to FTD and ALS, the ones which are better equipped to clear away protein waste survived, whereas the ones that didn't died.
"We then took a closer look at why these cells might be surviving despite the harmful proteins building up."
This was only possible thanks to a technology - called single-cell RNA sequencing - that allowed Dr Niccoli to examine how individual nerve cells behaved. This meant she could also study the subtle differences between resilient nerve cells compared to ones that died.
"Thanks to this technique that's allowed us to zoom in on individual brain cells in flies, we've also found that resilient nerve cells had higher activity of a protein involved in clearing waste. When we boosted this protein - called Xbp1 - in flies, it helped the fly brains cope with the toxic effect of the protein clumps caused by the C9orf72 mutation," she said.
"This suggests that, in flies at least, boosting Xbp1 activity could protect against this genetic change. We still don't know though whether this will have the same effect in human nerve cells."
Creating a map of individual brain cell activity like this is possible in flies, which have much smaller brains than humans. Right now, it is not clear if the same resilience principles seen in flies applies to humans, but further research could reveal more answers.
Dr Niccoli said: "Our next steps will be to look at whether boosting proteins involved in protein clearance increases resilience against C9orf72 changes in human nerve cells grown in the lab, and in mouse studies. Then we will have a better idea whether targeting Xbp1 or similar proteins in humans could help us discover new medicines for FTD or ALS."
Dr Jacqui Hanley, Head of Research Funding at Alzheimer's Research UK, commented on Dr Niccoli's new research: "Dr Niccoli's work continues to shed light on our understanding around a rare type of dementia.
"It's still too early to say whether boosting levels of the Xbp1 protein or similar proteins may help protect against FTD in humans. But identifying these molecular processes behind resilience is a vital first step towards finding new dementia treatments.
"Alzheimer's disease, the most common cause of dementia, has seen some recent successes with new treatments. But we desperately need a variety of medicines that can stop multiple complex diseases in the brain from progressing into other types of dementia, like FTD.
"Alzheimer's Research UK is committed to fund researchers like Dr Niccoli, who are helping us to build a bigger picture around the complex diseases that cause dementia so one day we can cure it."
