Summary: A collaborative neurobiology study uncovered a cellular mechanism tied to the severe, rapid progression of multiple sclerosis (MS). Published by a multidisciplinary team analyzing human post-mortem brain tissue, the research reveals that accelerated neurological decline is heavily driven by “foamy microglia”, brain immune cells that become pathologically overwhelmed and structural failures after absorbing excessive amounts of damaged myelin fat.
This discovery shifts the clinical understanding of MS past simple inflammatory models, offering concrete targets for metabolic drug development and predictive spinal fluid biomarkers.
Key Facts
- The Microglia Metamorphosis: Microglia are the brain’s resident immune cells responsible for clearing cellular waste and facilitating tissue repair. In rapidly deteriorating MS patients, these cells absorb so much broken-down myelin fat that they transform into abnormal, lipid-bloated structures known as “foamy microglia”.
- The Overload Bottleneck: While attempting to clear central nervous system damage, the microglia become completely overwhelmed by their own waste-processing systems. Once overloaded with lipid droplets, they lose their ability to heal tissue, worsen localized chronic inflammation, and actively counteract neurological recovery.
- Molecular Divergence: Inflammatory lesions packed with foamy microglia display radically different molecular signatures compared to standard MS lesions. Multi-omic mapping revealed that these foamy clusters harbor specific, destructive lipid profiles that perpetuate chronic, aggressive inflammatory states.
- The Post-Mortem Audit: Investigators mapped these abnormal patterns by analyzing brain lesions from 28 deceased MS patients via the Netherlands Brain Bank. They utilized advanced spatial technologies to simultaneously measure gene activity, protein expression, and fat concentrations within the exact same inflammatory tissue sites.
- Cerebrospinal Fluid Biomarkers: The study identified distinct fat molecules associated with foamy microglia that can potentially be harvested and measured in patients’ cerebrospinal fluid. This discovery paves the way for future diagnostic biomarkers to flag high-risk patients long before rapid paralysis sets in.
- Targeting Fat Metabolism: These findings align with ongoing pharmaceutical developments evaluating novel compounds designed to regulate lipid metabolism and halt chronic lesion expansion, with select therapies already entering clinical trials in collaboration with Roche.
Source: KNAW
Researcher Daan van der Vliet, together with colleagues from the Netherlands Institute for Neuroscience, Leiden University, and Utrecht University, has discovered an important mechanism that may be linked to severe progression of multiple sclerosis (MS). In brain tissue from patients with rapidly progressing MS, they found large numbers of abnormal immune cells overloaded with fat droplets.
The study offers new leads for treatments as well as biomarkers that could better predict disease progression.
Why does one patient deteriorate rapidly while another does not?
In MS, the fatty insulating layer surrounding nerve fibers (myelin) is broken down in the brain and spinal cord. This can lead to neurological symptoms such as difficulties with walking and vision.
MS progresses differently in every patient. Some people live for decades with relatively mild symptoms, while others become severely paralyzed at a young age. Researchers have therefore long tried to understand what causes these differences.
In the new study, the scientists focused on microglia: immune cells in the brain that clear waste and help repair damaged tissue. In MS patients, however, these cells change shape. They become filled with fat droplets, giving them a foamy appearance. Researchers call these cells “foamy microglia.”
“We found that patients with large numbers of these foamy microglia had a more severe disease course more frequently,” says researcher Daan van der Vliet.
Cleanup cells that become overwhelmed
Under normal circumstances, microglia help clean up damage in the brain. In MS, however, this task may sometimes become too big. The researchers believe the cells absorb so much damaged myelin that they eventually become overwhelmed by their own waste-processing system.
“These cells are probably trying to do something good: clearing up damage,” Van der Vliet explains. “But they become overloaded, so to speak. As a result, they can no longer effectively contribute to repair.”
The researchers also discovered that brain inflammations containing foamy microglia behave very differently at the molecular level from MS inflammations without these cells. For example, they contain specific fats involved in chronic inflammatory responses.
A new perspective on MS
For a long time, inflammation was thought to be the driving force behind disease progression, but the study also shows that MS may be more complex than that alone. According to the researchers, their work points to a more subtle process.
“It does not appear to be simply about the inflammatory response alone,” says Van der Vliet. “These cells are probably attempting to clear damage and promote repair, but that process fails, worsens inflammation, and counteracts recovery.”
Advanced techniques and human brain tissue
For the study, the scientists analysed brain tissue from 28 deceased MS patients who had donated their brains to the Netherlands Brain Bank. The team combined several advanced techniques that simultaneously examined gene activity, proteins, and fats within the same MS inflammatory lesions.
According to the researchers, the combination of modern technology and detailed knowledge of brain pathology was especially crucial.
“Today we have incredibly sophisticated techniques that can map the brain in great detail,” Van der Vliet says.
“The technologies are fantastic, but they tell you relatively little if you cannot connect them to pathology in brain tissue. Precisely because brain tissue has been carefully studied and classified for years by the Netherlands Brain Bank, we were able to recognize these abnormal patterns.”
A possible step toward more personalized treatment
In the long term, the discovery may help improve predictions of MS disease progression. The researchers found indications that certain fats associated with foamy microglia can also be measured in patients’ cerebrospinal fluid.
“That opens the possibility of developing biomarkers in the future that could help doctors identify earlier which patients are at risk of rapid decline — and which treatment would suit them best.”
In addition, the findings align with ongoing developments in new medicines targeting fat metabolism and chronic lesion expansion in MS. Some of these drugs are already being investigated in clinical studies in collaboration with Roche.
Funding: The research was funded by two Gravitation programs: the Institute for Chemical Immunology (ICI) and the Institute for Chemical NeuroScience (iCNS).
Key Questions Answered:
A: It is a classic case of system overload. Microglia enter MS lesions with good intentions: to clean up the fatty myelin debris left behind by autoimmune attacks. However, when the breakdown is too massive, these cells eat far more fat than their internal waste-processing systems can handle. They get bloated into “foamy microglia,” get stuck, and stop helping with brain repair.
A: By using advanced, high-definition technology on perfectly preserved tissue from the Netherlands Brain Bank, scientists mapped the exact toxic fats created inside these foamy cell clusters. Because these specific, signature fats leak into the surrounding cerebrospinal fluid, doctors can develop non-invasive spinal taps to spot these destructive markers in living patients early.
A: Not the wrong problem, but an incomplete one. For a long time, MS progression was viewed purely through the lens of immune-driven inflammation. This study proves that rapid decline is a more complex, subtle metabolic failure. This is exactly why the field is moving toward brand-new drugs, including candidates in clinical trials with Roche, that specifically target fat metabolism to protect the brain.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this multiple sclerosis research news
Author: Eline Feenstra
Source: KNAW
Contact: Eline Feenstra – KNAW
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Foamy microglia link oxylipins to disease progression in multiple sclerosis” by Daan van der Vliet, Xinyu Di, Tatiana M. Shamorkina, Claire Coulon-Bainier, Anto Pavlovic, Iris A. C. M. van der Vliet, Yingyu Zeng, Will Macnair, Noëlle van Egmond, J. Q. Alida Chen, Aletta M. R. van den Bosch, Hendrik J. Engelenburg, Dennis Wever, Matthew R. J. Mason, Wouter P. F. Driever, Berend Gagestein, Elise Dusseldorp, Marco van Eijk, Uwe Grether, The Netherlands Brain Bank, Amy C. Harms, Thomas Hankemeier, Ludovic Collin, Albert J. R. Heck, Inge Huitinga & Mario van der Stelt. Nature Neuroscience
DOI:10.1038/s41593-026-02302-3
Abstract
Foamy microglia link oxylipins to disease progression in multiple sclerosis
Multiple sclerosis (MS) is a chronic neuroinflammatory disease in which demyelinating white matter lesions accumulate and expand, driving irreversible disability. Here we identify a distinct population of foamy GPNMB+ microglia/macrophages associated with lesion expansion in secondary progressive MS.
Using integrated lipidomic, transcriptomic, proteomic, chemical proteomic and histological analyses of human postmortem MS lesions, we show that lesions containing foamy microglia/macrophages exhibit disrupted lipid metabolism, lysosomal stress and markers associated with heightened phagocytosis and antigen presentation without classical pro-inflammatory signatures.
These lesions are enriched for oxylipins, bismonoacylglycerolphosphates and cholesterol esters, and are associated with increased B cell infiltration and IgG1.
Monoacylglycerol lipase (MAGL), a lipid-metabolizing enzyme enriched in lesions with foamy microglia/macrophages, emerged as a potential therapeutic target. Inhibition of MAGL promoted lesion recovery and reduced microgliosis in a mouse model of demyelination.
Finally, oxylipins in cerebrospinal fluid correlate with the proportion of foamy lesions, suggesting potential biomarkers for progression.
Our findings implicate disturbed lipid metabolism in chronic MS pathology and suggest that foamy microglia/macrophages are an interesting cell type to target for progressive disease.
