We write about change — about impact and consequences, about discoveries and the people behind them. This time, we introduce you to Roosmarijn Vandenbroucke, a discovery scientist at IRC-VIB and a professor at Ghent University. She gives us an eagle’s-eye view of her group’s latest research, which has the potential to impact the management of patients with neurodegenerative and neuroinflammatory diseases.
Neurodegenerative disorders such as Alzheimer’s and Parkinson’s are among the most devastating in terms of the effect on quality of life, as well as the financial and social costs. In fact, it has been suggested that such diseases will displace cancer as the second-leading cause of mortality (after cardiovascular diseases). Major funding arms, such as Horizon 2020 and the EU’s Joint Programme on Neurodegenerative Disease Research, have poured more than 30 million euros into research to help stop these diseases.
Breaking barriers at the age of 33
The human brain engages in a constant, highly controlled exchange of specific molecules — good and bad — with the rest of the body. The blood-brain barrier protects the brain from most blood-borne toxins, but it also significantly hinders the delivery of therapeutics to the brain. However, the choroid plexus, a tiny collection of cells in the cavities of the brain, creates another barrier — between the blood and the cerebrospinal fluid (CSF), which bathes the brain and the spinal cord. Shortly after Vandenbroucke initiated her postdoctoral work in the lab of Claude Libert (VIB, UGent), her team discovered that changes in the blood — sepsis, for instance — affected the blood-CSF barrier. Since then, the Vandenbroucke team has made fundamental contributions to a unique research line, becoming one of the few labs in the world that can routinely work with the CP and CSF.
The choroid plexus is extremely important in brain homeostasis, as it produces the cerebrospinal fluid. How this structure functions and influences brain homeostasis has become my focus.
‘’When I started the work five years ago,” Vandenbroucke recalls, “only a few of us were talking about the choroid plexus at conferences focusing on the blood-brain barrier. But in the last three years a lot of literature has been coming out, and the field is changing a lot.”
Research in this area was slow to develop in part because of the technical challenges imposed by working with something the size of the tip of a needle. “You need to be able to isolate the cerebrospinal fluid to study the CP function and how it changes the CSF composition,” Vandenbroucke explains. “When we started the work several years ago, the isolation of CSF was a big issue. Mice have only about a drop of CSF, and you can isolate only a little bit of it. The isolation of the choroid plexus as such is also quite difficult. But now we are able to routinely collect CSF samples from mice without blood contamination. We can isolate CP tissue and perform RNA sequencing, proteomics and electron microscopy on both CP and CSF samples.”
Why does it matter?
Cerebrospinal fluid is routinely used in the clinic for diagnosis of infectious diseases, bleeding in the brain, tumors and autoimmune disorders such as multiple sclerosis.
‘’People often forget that the composition of the cerebrospinal fluid might be mainly a reflection of CP function. Two-thirds of the CSF is produced by the CP,” says Vandenboucke. “But for some reason, if people see changes in the CSF, they see this as reflection of brain changes and they do not consider that these might be caused by the CP. This cell layer actively transports molecules from the blood into the CSF. This is a controlled process and ensures that there is no leakage possible from the blood to the brain. Additionally, the CP also synthesizes molecules that are secreted in the CSF. Therefore, one can imagine that if the CP cells sense inflammation, these processes might change, affecting the CSF composition.”
‘Brain and body inflammation might affect the CSF composition. This is also a way in which inflammation of the body might affect neuroinflammatory and neurodegenerative diseases, like Alzheimer’s.
Potential therapeutic venues
In their latest research, published in EMBO Molecular Medicine, Vandebroucke’s team has reported another novel blood-to-brain communication system, linking acute body inflammation with septic shock — the inability of the brain to dampen the inflammatory response, resulting in organ failure. The scientists showed that the CP senses inflammation in the blood and signals to the brain by releasing extracellular vesicles, or EVs.
We need to focus on the extracellular vesicles. Until a few years ago, we thought that these vesicles were merely released because cells needed to get rid of them.
“Only recently, scientists got interested in EVs and saw they contain messages,” stresses Vandenbroucke. “The field of understanding their biological function is really new. The vesicles are secreted at one place, and they have an effect much further, making it very difficult to study this process in vivo. The lack of good mouse models to study the biological functions of EVs is still a major problem in this field.”
In neuroscience, EVs are being considered for use as a therapeutic delivery system to treat neurogenerative diseases. Might these vesicles have true potential as a drug delivery system?
“It will never be easy to use EVs as a drug delivery system,” Vandenbroucke admits. “They carry a lot of miRNAs and proteins. Some of them have good effects, but some of them might have bad effects. Instead, our focus is to identify which parts of the EV are responsible for targeting the brain. What part of the vesicle enables it to cross the blood-CSF or the blood-brain barrier? One could use this mechanism and transfer it on to a safer system, such as lipoplexes or other nanoparticles. In addition, concerning the Alzheimer’s field, it is not yet clear whether the EVs are good or bad. This is something that we are looking into.”
The Vandenbroucke group is also looking into ways to block vesicle production by the CP.
“Septic shock is often so acute and so extreme that it is difficult to intervene, but it might be possible to prevent the long-term effects, such as cognitive decline. People sometimes suffer months and years after having severe sepsis,” says Vandenbroucke. “Blocking vesicle production might not protect against mortality, but it may be important in countering the long-term effects of sepsis.”
Balusu et al. Identification of a novel mechanism of blood–brain communication during peripheral inflammation via choroid plexus-derived extracellular vesicles. EMBO Molecular Medicine (2016) e201606271