8 November 2016

The mysterious role of fats in the brain

Alzheimer’s disease is, in many ways, still a mystery for researchers. Amyloid beta is known to play a major role in the brains of Alzheimer’s patients, but reducing the levels of this protein does not seem to help. At the same time lipids, or fats, in the brain appear to be implicated with the disease in some way. A group of researchers at Maastricht University are trying to find out how. Working with colleagues in the Netherlands and abroad, they are focusing on an existing drug for multiple sclerosis (MS). Could it also be used to treat Alzheimer’s? With a view to the national charity collection of the Dutch Alzheimer Foundation this week, we speak to Pilar Martinez about her research. 

Alzheimer’s disease often begins with forgetfulness and memory problems. Speaking and thinking gradually become more difficult, and the patient’s character and behaviour usually change as well. This is due to a reduction in the number of brain cells and in the ability of these cells to communicate with one another. Our brains are largely made up of fats (lipids). One specific type are sphingolipids, named after the mythological Sphinx for their enigmatic nature. Scientists suspect there is an imbalance in the sphingolipids in the brains of people with Alzheimer’s, as this has already been detected in the blood and brain fluid. “We want to know why these lipid levels change when something is going wrong in the brain”, says Pilar Martinez, who leads a research group at Maastricht University.

€1.4 million grant
Martinez coordinates a large research project involving universities both in the Netherlands and abroad. In December 2014 they were awarded a €1.4 million grant from the Memorabel programme of ZonMW, a national health organisation, to fund four years of research into the role of lipids in Alzheimer’s. One of the research lines focuses on testing a drug already used by MS patients. “I noticed that this drug specifically targets sphingolipids, and because it’s an existing medicine, it may allow us to circumvent the enormously long process involved in the development of a new drug. If it works. So that’s what we’re now studying in Maastricht: do mice with Alzheimer’s benefit from this medicine? Does their lipid metabolism and their behaviour improve?” The researchers in Rotterdam and Amsterdam are studying the lipid levels as well as the proteins that help to produce these lipids in the brains of deceased patients who had a certain type of dementia. There may well be differences from one type of dementia to the next, which can in turn affect whether or not the MS drug works.

Early detection
Another part of the research focuses on the gene ApoE4, carried by approximately 15% of the population. People with this gene have an increased risk of developing Alzheimer’s, but it is not yet clear why. ApoE4 probably also plays a role in lipid metabolism – but again, its exact role remains shrouded in mystery. “With another research grant I’m planning to investigate lipid changes in the blood collected from 400 Limburgers during the large-scale Maastricht Study. We’re hoping to come closer to developing a means of detecting Alzheimer’s at an earlier stage. Not only can we not treat the disease well, at present we also can’t detect it early. Identifying a ‘biomarker’, a sign in the blood that the disease is developing, would be a great help in fighting the symptoms earlier and hopefully more effectively.”

Testing drugs
Initial results from the study on the first MS medicine focused on sphingolipids are expected in late February 2017. “We might manage to target the right lipid immediately, but there may be others that are more effective. That’s why this type of research needs to continue. If the effect is not as strong as hoped, you want to study comparable lipids in the brain. Between us and the other participating universities, we have the infrastructure to be able to test any drug that acts on lipids. But there are so many lipids and there are more drugs still in development.”

Long-term perspective
Martinez takes seriously the duty to put her research funding to good use. Often it comes from government agencies, and thus ultimately taxpayers. “I hope people understand that this type of research requires sustained effort and it’s important to keep on going. In the four years covered by this €1.4 million, we obviously won’t discover the cure for Alzheimer’s. We can make a promising start, but then we have to acquire yet more grants to be able to continue our work. If people are interested in supporting this type of research, I invite them to get in touch with the Hersenstichting [Brain Foundation].” In late November the European Commission is also expected to decide on establishing an international platform in the Euregion, where companies as well as researchers from the universities in Maastricht, Aachen and Liège will work together to gain greater insight into the role of lipids in heart and brain diseases. Martinez: “It would be the first in the world, and so would also give the region an economic boost.”

By Femke Kools

Basic and applied research
Pilar Martinez’s research falls in some respects into the category ‘basic research’, the importance of which scientists repeatedly emphasise when it comes to making scientific strides in the future. She is trying to understand how our brain cells work. In this type of research, it is often not clear from the outset exactly how it might benefit patients, but in the past the insights gained from such research have ultimately led to the development of new treatments. This latter stage is called ‘applied research’; research that can be directly translated into a treatment or some other social improvement (such as the MS drug, in this case).

CV Pilar Martinez
Pilar Martinez (Spain, 1972) has worked at Maastricht University since 2002. A molecular biologist, she leads the Nervous System Neuroinflammation and Autoimmunity research group in the Department of Psychiatry and Neuropsychology. She received her PhD cum laude from the University of Valencia in 2003. She has been awarded numerous grants, including a Marie Curie Fellowship, an Aspasia grant for female researchers in the Netherlands and various grants from organisations such as the International Foundation for Alzheimer’s Research (ISAO/Alzheimer Nederland).