When we think about cholesterol, we often imagine clogged arteries and heart disease. But behind the scenes, this same molecule plays a critical role in our brain and nervous system.
When myelin breaks down in conditions like multiple sclerosis (MS), can boosting cholesterol levels help repair the damage? The answer, it turns out, is more complex than scientists initially thought.
Unlike other organs, the brain maintains its own independent cholesterol pool. The blood-brain barrier (BBB) acts as a strict gatekeeper, preventing cholesterol from the bloodstream from entering the central nervous system (CNS) under normal conditions 2 .
This means the brain must produce all the cholesterol it needs locally.
Myelin, the fatty insulating substance that wraps around nerve fibers, is exceptionally rich in lipids. In fact, lipids constitute approximately 80% of myelin's dry weight 6 .
Cholesterol is one of the three major lipid fractions in myelin, along with phospholipids and glycolipids 6 . It provides structural integrity to the myelin sheath and is considered a rate-limiting factor for new myelin formation 2 5 .
To investigate whether raising systemic cholesterol levels could impact demyelinating diseases, researchers conducted a meticulous study using Theiler's murine encephalomyelitis (TME), a viral model that shares important characteristics with multiple sclerosis 1 3 .
The research team designed their experiment to comprehensively assess the relationship between dietary cholesterol, demyelination, and remyelination.
They used SJL/J mice, which are susceptible to TME virus infection. This infection leads to progressive loss of motor function and demyelination in the spinal cord, mimicking aspects of MS 1 .
Mice were divided into two feeding groups starting 13 days before infection:
Both groups were infected with the BeAn strain of TME virus. Researchers sacrificed animals at multiple time points post-infection (up to 196 days) to study both acute and chronic phases of the disease 1 .
The findings yielded unexpected insights into the relationship between systemic cholesterol and CNS repair:
| Group | Gene Expression Pattern | Interpretation |
|---|---|---|
| TMEV-infected mice | Overall down-regulation | Suggests reduced local cholesterol production is a marker of demyelination |
| Mock-infected mice | Normal expression | Baseline cholesterol synthesis in healthy nervous tissue |
| Lipid Component | Change in TMEV-infected mice | Interpretation |
|---|---|---|
| Galactocerebroside | Reduced | Indicates loss of myelin-specific lipids in chronic demyelination |
| Sphingomyelin | Reduced | Further evidence of specific myelin lipid loss |
| Cholesterol | No significant quantitative loss | Suggests cholesterol may be preserved despite demyelination |
| Disease Parameter | Effect of Paigen Diet | Interpretation |
|---|---|---|
| Clinical course | No significant difference | Dietary cholesterol didn't worsen or improve motor performance |
| Inflammatory response | No significant difference | High cholesterol didn't exacerbate inflammation |
| Demyelination amount | No significant difference | Dietary cholesterol didn't protect against myelin damage |
| Remyelination amount | No significant difference | Dietary cholesterol didn't enhance myelin repair in this model |
The most striking finding was that despite successfully inducing systemic hypercholesterolemia and hepatic lipidosis (fatty liver) with the Paigen diet, the high dietary cholesterol intake led to no significant differences in the clinical course, inflammatory response, or the extent of demyelination and remyelination in the spinal cords of TMEV-infected animals 1 3 .
| Research Tool | Function in Experiment |
|---|---|
| Theiler's Murine Encephalomyelitis Virus (TMEV) | Induces an inflammatory, demyelinating disease in the spinal cord that serves as an animal model for MS. |
| Paigen Diet | A specially formulated high-fat, high-cholesterol diet used to induce systemic hypercholesterolemia in research animals. |
| Affymetrix GeneChip Microarrays | Technology used to analyze the expression levels of thousands of genes simultaneously, revealing pathways affected by disease. |
| High-Performance Thin Layer Chromatography | A technique used to separate and quantify different lipid species in tissue samples, such as those from spinal cord. |
| Immunohistochemistry | A method using antibodies to visually detect specific cell types (e.g., immune cells, astrocytes) or damage markers in tissue sections. |
The conclusion that systemic cholesterol levels do not affect CNS remyelination presents a fascinating scientific puzzle, particularly because other studies have reached different conclusions.
Research using the cuprizone model of demyelination found that dietary cholesterol supplementation did enhance remyelination 5 .
In that model, the blood-brain barrier was compromised, allowing cholesterol to enter the CNS and directly support oligodendrocyte precursor cells 5 .
Future strategies may need to focus on manipulating local cholesterol metabolism within the CNS rather than increasing systemic levels.
Promising approaches include targeting specific cells like microglia, which upregulate cholesterol synthesis during remyelination 2 , or investigating drugs that reduce cholesterol ester accumulation 4 .
The discovery that systemic cholesterol levels do not directly influence demyelination or remyelination in the TME model challenges simplistic assumptions about dietary cholesterol and brain repair. It underscores the sophistication of the brain's independent cholesterol system and reminds us that the path to effective therapies requires unraveling complex, localized metabolic processes. As research continues to explore how to manipulate these processes, we move closer to potentially unlocking new treatments for debilitating demyelinating diseases like multiple sclerosis.
This article was based on findings published in Brain Pathology (2015) and incorporates recent research from the Journal of Neuroinflammation (2025) and Nature Communications (2017).