Summary: A collaborative neurobiology study has identified a cellular mechanism linked to the rapid and severe progression of multiple sclerosis (MS). An international team analyzed human post-mortem brain tissue and found that an overaccumulation of damaged myelin lipids transforms brain immune cells into dysfunctional, lipid‑laden “foamy microglia.” These cells become metabolically overwhelmed, lose their repair functions, and actively drive chronic inflammation and lesion expansion.
This finding moves the clinical view of MS beyond a purely inflammatory model and points to specific lipid metabolic pathways and cerebrospinal fluid biomarkers as practical targets for new therapies and earlier risk detection.
Key Facts
- The microglial transformation: Microglia are the brain’s resident immune and cleanup cells. In patients with rapidly advancing MS, many microglia become engorged with fat droplets from degraded myelin and adopt a distinctive “foamy” appearance linked to poor clinical outcomes.
- Metabolic overload and functional failure: As microglia ingest excessive amounts of myelin-derived lipids, their lysosomal and lipid-processing systems become stressed. Overloaded microglia stop supporting tissue repair, maintain a harmful local environment, and contribute to ongoing lesion growth.
- Distinct molecular signatures: Lesions rich in foamy microglia show markedly different lipid, RNA, and protein profiles compared with conventional MS lesions. These foamy clusters are enriched in oxylipins, bismonoacylglycerolphosphates and cholesterol esters—lipid species associated with persistent inflammation.
- High-resolution post-mortem mapping: The team examined lesions from 28 donated brains using integrated spatial methods that measured gene expression, protein levels, and lipid content in the exact same tissue regions, enabling precise correlation of cellular state with molecular changes.
- Cerebrospinal fluid biomarkers: Specific lipids linked to foamy microglia were detected in cerebrospinal fluid (CSF) and correlate with the presence of foamy lesions, offering a promising route to develop diagnostic biomarkers that could flag patients at high risk of rapid progression.
- Therapeutic implications: The study highlights disrupted lipid metabolism as a druggable process. Monoacylglycerol lipase (MAGL), a lipid‑processing enzyme enriched in foamy lesions, emerged as a candidate target; MAGL inhibition improved lesion recovery and reduced microglial activation in experimental models. Several therapeutic programs targeting lipid metabolism are already under clinical investigation.
Source: KNAW
Researcher Daan van der Vliet and collaborators from the Netherlands Institute for Neuroscience, Leiden University, and Utrecht University identified a mechanism that may underlie severe MS progression. In brain tissue from patients who experienced rapid decline, the researchers observed many microglia overloaded with fat droplets.
Their work points to new avenues for both treatments and predictive biomarkers to better stratify patients by risk and tailor interventions sooner.
Why do some people deteriorate quickly while others do not?
Multiple sclerosis damages the myelin sheath—the fatty insulating layer around nerve fibers—in the brain and spinal cord. This demyelination can cause impairments in vision, mobility, balance and other neurological functions. Disease trajectories vary widely: some people maintain mild symptoms for decades, while others experience steep, early decline. The study focused on whether microglial behavior helps explain these differences.
Microglia normally clear debris and support repair. Yet in some MS lesions they become filled with myelin‑derived lipids and adopt a foamy morphology. According to Daan van der Vliet, patients whose brains contained many foamy microglia were more likely to have a severe clinical course.
Cleanup cells that become overwhelmed
Under healthy conditions, microglia remove damaged material and help restore tissue. When damage is extensive, however, the incoming lipid load can exceed the cells’ processing capacity. Chronically overloaded microglia suffer lysosomal stress, lose their reparative roles, and promote a localized environment that sustains chronic inflammation and lesion expansion.
The researchers also showed that lesions with foamy microglia carry molecular signatures distinct from other inflammatory lesions—signatures dominated by lipid species linked to persistent immune activation and altered antigen presentation.
A broader view of MS progression
Historically, MS progression has been framed primarily as an inflammatory problem. This study adds nuance: rapid decline appears to involve a metabolic failure within microglia that transforms a reparative process into a driver of chronic pathology. The authors emphasize that foamy microglia may be both a marker and a mediator of aggressive disease.
Advanced techniques and well-characterized human tissue
The team combined lipidomics, transcriptomics, proteomics, chemical proteomics, and high-resolution histology on lesions from 28 donors provided by the Netherlands Brain Bank. Integrating these technologies with decades of pathological expertise made it possible to detect and validate the abnormal foamy patterns and their molecular correlates.
Toward personalized care
Because particular lipid molecules associated with foamy microglia are detectable in cerebrospinal fluid, clinicians may eventually use such markers to identify patients at risk for rapid progression. This would enable more targeted treatment choices early in the disease course. In parallel, drugs aimed at correcting lipid metabolism—such as MAGL inhibitors—offer a mechanistically grounded strategy to limit lesion expansion and preserve function.
Funding: The study was supported by the Gravitation programs Institute for Chemical Immunology (ICI) and Institute for Chemical NeuroScience (iCNS).
Key Questions Answered:
A: Microglia normally clear myelin debris, but when the amount of broken-down myelin is extreme they ingest far more lipids than they can process. The resulting lysosomal and metabolic stress converts them into stationary, lipid‑filled “foamy microglia” that no longer support repair and instead promote chronic lesion growth.
A: High-resolution molecular mapping of well-preserved post-mortem lesions revealed specific lipid fingerprints associated with foamy microglia. These lipids are present in cerebrospinal fluid, which means they could be developed into non‑invasive biomarkers to detect high‑risk patients earlier.
A: Not necessarily wrong, but incomplete. Traditional anti-inflammatory therapies address immune activation that contributes to MS. This study indicates that, for rapid progression, metabolic dysfunction in microglia plays a key role. Combining inflammation control with therapies that correct lipid metabolism may better prevent lesion expansion and disability.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The original journal paper was reviewed in full.
- Additional context was added by our editorial 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 (paraphrased)
Foamy microglia link oxylipins to disease progression in multiple sclerosis
Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by accumulating and expanding demyelinating white matter lesions that drive irreversible disability. The study identifies a distinct population of foamy GPNMB-positive microglia/macrophages associated with lesion expansion in secondary progressive MS.
By integrating lipidomics, transcriptomics, proteomics, chemical proteomics and histology on human post-mortem MS lesions, the researchers show that foamy lesions display disrupted lipid metabolism, lysosomal stress, and signatures of enhanced phagocytosis and antigen presentation without classic pro‑inflammatory profiles.
These lesions are enriched in oxylipins, bismonoacylglycerolphosphates, and cholesterol esters and are associated with increased B cell infiltration and IgG1. Monoacylglycerol lipase (MAGL), a lipid‑metabolizing enzyme elevated in foamy lesions, emerged as a therapeutic candidate: MAGL inhibition improved lesion recovery and reduced microgliosis in an experimental demyelination model.
Finally, specific oxylipins in cerebrospinal fluid correlate with the proportion of foamy lesions, indicating potential biomarkers for disease progression. Overall, the findings implicate disturbed lipid metabolism in chronic MS pathology and nominate foamy microglia/macrophages as a priority cell type for targeting progressive disease.