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TREM2: Where are we now?
By Dr Emma O'Brien | Tuesday 20 January 2015
Yesterday, Dr Rita Guerreiro was awarded the great honour of European Researcher of the Year, fighting off stiff competition from dementia researchers across the continent. This fantastic achievement recognised her groundbreaking discovery in 2012; variations in the DNA code of a gene involved in immune system regulation, called TREM2, can increase the risk of Alzheimer’s disease three fold. This discovery set the dementia research community a-light, opening up a Pandora’s Box for scientists discussing the role of the immune system in Alzheimer’s. While this wasn’t the first time the immune system was implicated in Alzheimer’s, it was the strongest suggestion yet that the body’s defence system may actually be involved in the progression of the disease, rather than purely a consequence of nerve cell damage in the brain. But identifying a risk gene was just the start. The genetic studies have spawned a wide range of projects trying to better understand the role of TREM2 in Alzheimer’s. Let’s take a look at some of the ongoing work that Alzheimer’s Research UK is proud to be funding.
The genetic discovery towards the end of 2012 has led to a flurry of activity probing the role of TREM2 in Alzheimer’s (click to enlarge)
What is TREM2?
TREM2 is a gene that codes for a protein of the same name produced by microglia – the brain’s immune defence cells. The TREM2 protein decorates the surface of microglia cells and regulates their response to infection and injury.
Dr Guerreiro, working with a global team of scientists, discovered that people who have a rare variation in DNA code that makes up their TREM2 gene are three times more likely to develop Alzheimer’s than those with the more common versions. This variation in the TREM2 DNA code – known as a mutation – means that the protein is assembled with the incorrect building blocks, leading to decreased function. Without TREM2 to keep microglia in check correctly, it’s thought that these immune cells become hyperactive. The immune response is the body’s weapon against damage and attack. But too much of a good thing can be dangerous and inflammation can frequently become the foe within.
About her award, Dr Guerreiro said:
“I’m really honoured to have received this award. The TREM2 genetic study came about as a result of hard work from a team of global scientists and I am proud to have led this work with Professor Hardy and our group here at UCL. It’s so exciting to see all the work that has come about as a result of the discovery and I look forward to the scientific community working together to find out more about TREM2 and the immune system in Alzheimer’s. I hope that these findings take us a step closer to finding treatments for the disease, which affects so many people around the world.”
Understanding the genetics of TREM2
The next step for Dr Guerreiro and other researchers was to look at the proteins that TREM2 interacts with. TREM2 does not sit in isolation on the microglial cell surface; it is a member of a complex of proteins involved in immune system regulation. In 2013, we funded Dr Guerreiro to start a Pilot Project exploring genetic variations in the other members in this regulatory complex. Working with Dr Angela Hodges, another Alzheimer’s Research UK Pilot Project grantholder, they set out to narrow in on other possible genetic changes that affect the molecular chain of events controlling TREM2. While this could highlight more risk genes for Alzheimer’s, the key aim is to understand more about the biology underpinning the disease. This deeper understanding could help find new treatments for the half a million people living in the UK with Alzheimer’s.
Microglia are the brain’s immune response cells.
Understanding the biological role of TREM2
While some teams have been focussing on the genetics of TREM2, others have started to look at how these changes to the function of TREM2 affect brain biology. Christina Murray, a new PhD student working with Dr Tammaryn Lashley at University College London, is looking at the levels of the TREM2 protein in donated human brain tissue. We’re funding Christina to investigate in whether changes in TREM2 alter the appearance and activity of microglia in response the amyloid plaques in Alzheimer’s. This will help her build a picture of the chain of events that drives Alzheimer’s and where TREM2 comes in.
In work getting under way in the coming weeks, Alzheimer’s Research UK Clinical Research Fellow, Dr Pablo Garcia Reitboeck, aims to use new stem cell technology to study microglia. Dr Garcia Reitboek will take skin cells from people who have the mutated version of TREM2 and turn these into microglia in a dish. He predicts that changes in the function of TREM2 alters the ability of microglia to ‘eat-up’ and clear the dangerous build-up of amyloid in the brain. He will also look at whether microglia with mutated TREM2 can trigger a harmful inflammatory response which damages nerve cells. By shedding greater light on these wayward microglial actions, researchers hope to find new ways to halt the damage in Alzheimer’s and keep precious brain cells healthier for longer.
The impact of the TREM2 discovery lies not so much in predicting who might get the disease; only 0.3% of the population carry the mutation. Rather, it suggests a new player in the biological chain of events that lead to Alzheimer’s. By honing in on the role of TREM2, as well as looking more broadly into the contribution of the immune system to the disease, researchers will find new approaches for treatments and new hope for those living with Alzheimer’s.
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About the author
Dr Emma O'Brien
Team: Science news
The resarch information that the U.K. have provided has been not only enlightening, but leaves one hopeful for a cure or treatment for Alzheimer’s. My mother was taken from me by this disease. Five years ago, my sister one year my junior was diagnosed with the first stage of this disease. Years before my mother died, I learned that she and all of her 8 other sibblings had diabetes and a form of dementia. My younger sister with the disease also has Type 2 Diabetes. I am one of 15 children, and half of us have Type 2 Diabetes, which now includes members among the next generation. I do not have diabetes. My boyfriend was recently diagnosed with Posterior Cortical Atrophy. I am heartbroken!
What, if any, treatments are proven effective in slowing down the progress of PCA? Please help me help my boyfriend. Where can we go for help in fighting this dreadful disease? He is losing all hope.
Hello. Thank you for the additional links to information on your Alzheimer’s research.
I reside in Florida. If you have any contacts in the U.S., especially in Florida, who have the latest information on treatments for Posterior Cordical Atrophy, I would appreciate receiving their contact information.
Many Sincere Thanks,
Terrylane Allen
Thank you for your comments. I’m sorry to hear about your personal experiences of dementia.
PCA is almost always caused by Alzheimer’s disease. Unlike typical Alzheimer’s disease PCA tends to first affect the back of the brain- which processes visual information, rather than the sides of the brain- which are involved in memory. As the same disease processes underlie PCA, the treatments prescribed for typical Alzheimer’s disease can be beneficial for people with PCA. While these treatments don’t slow the progression of the disease, they often help in improving some of the symptoms. You can find more details about these medications here: https://alzheimersresearchuk.org/dementia-types/10000/alzheimers-disease/#acc2/ Physiotherapy or occupational therapy can sometimes be beneficial for people with PCA in developing ways to live with, or compensate for, some of their symptoms. Some people with PCA may also benefit from visual aids and resources developed for people with sight problems. Your friend’s doctor is the best person to offer advice about these treatments. We’re continuing to invest in PCA research so that we can develop better ways to help people affected by the condition. You can read more about some of this research in this blog post: http://www.dementiablog.org/when-alzheimers-steals-your-sight/
While we’re not best placed to provide information about support services are available for people with PCA in Florida, I know that the Alzheimer’s Association offers advice and support to people with dementia in the U.S. – you can find out more about them on their website http://www.alz.org/ or by calling their 24/7 helpline on 1.800.272.3900.
The link between diabetes and Alzheimer’s disease is an important area of research. You can read a little about some of the work we have funded in this area here: https://alzheimersresearchuk.org/news-detail/10176/Dementia-study-in-Coleraine-raises-Alzheimers-treatment-hope/ . Other researchers have built on this research and Alzheimer’s treatments based on current diabetes medications are in clinical trials at the moment.
I feel very sad that my husband was diagnosed in 1990 with Pick’s dementia but to me there seems to be no further advancement since then. My husband battled with this dreadful disease for 15 years.
Very distressing illness, as are all of the dementias.
So I recently learned through consumer genetic testing that I may have the rare TREM2 missense mutation. Of course I’m upset about this. I understand it greatly increases my AD risk, even though I have zero family history. Is there anything I can do? Is coffee likely to have the same (supposed) protective effect for me as it might for other more traditional AD sufferers? Does my gender (male) make me any less likely to get the disease, since I understand females tend to be at greater risk? Any thoughts would help me now.
We would recommend that you make an appointment to discuss your concerns and the result of the genetic test with your GP. Your GP will be able to talk to you about this and arrange for any referrals to other clinics to help you. We have lots of information about reducing the risk, genetics, treatments and other frequently asked questions in our helpful information section of our website: https://alzheimersresearchuk.org/about-dementia/helpful-information/ which may be of help to you. Many people live well with dementia but we recommend, first and foremost, that you talk to your GP about your result and your concerns.
what are the symptoms of early Dementia? I have had 2 people ask me if my husband is losing his memory, including his sister. I have noticed a difference in him, also a blank look in his eyes when I ask him something that he does not remember. But, then there days he seems absolutely normal. What should I do?