Neurodegeneration: The role of cholesterol metabolism

• A recent study investigated the link between neurodegenerative disease proteins and defective cholesterol metabolism.
• The results indicate that faulty cholesterol metabolism is a common feature among people living with neurodegenerative conditions.
• The researchers suggest that restoring cholesterol levels may become a beneficial new strategy in the treatment of certain neurodegenerative conditions.

Cholesterol, an essential component of the body, helps in maintaining the integrity of cell membranes. It also helps synthesize hormones, vitamin D, and other important cell substances.

In the body, about 23–25% of total cholesterol is in the cells of the brain. Here, it helps in enriching the myelin sheath, which covers nerve cells and is important in nerve signal conduction and transmission. This transmission is necessary for coordinating bodily functions, such as walking and talking.

Damage to the myelin sheath may slow or reduce transmissions, resulting in neurological problems. Recently, researchers set out to study why specific neurodegenerative conditions result in the loss of protective cholesterol-rich myelin sheaths.

Neurodegenerative diseases and cholesterol

Researchers from Yong Loo Lin School of Medicine at the National University of Singapore recently discovered that in the absence of a protein called transactive response DNA binding protein (TDP-43), brain cells cannot maintain protective myelin sheaths.

Their research reveals that TDP-43 protein, which is involved in conditions such as amyotrophic lateral sclerosis and frontotemporal dementia, influences cholesterol metabolism in the brain. It also showed that cholesterol synthesis and absorption play a vital role in myelin sheath formation.

Shuo-Chien Ling, one of the study’s authors, explained to Medical News Today why he decided to investigate the links between TDP-43 and cholesterol metabolism:

“We investigated the link between TDP-43 and cholesterol metabolism based on the experimental data that we got from our [past] work in mice with TDP-43 deleted from oligodendrocytes.” Oligodendrocytes protect and myelinate neurons, consequently improving transmission speed.

“Specifically, we found that mice with oligodendrocytes lacking TDP-43 develop progressive neurological phenotypes leading to early lethality. These phenotypes were accompanied by the death of oligodendrocytes and progressive loss of myelin,” he added.

Imbalance in cholesterol regulation is a common feature associated with neurodegenerative conditions, such as Alzheimer’s disease and Parkinson’s disease.

In a podcast, Dr. Keith Josephs, a consultant in the Department of Neurology at the Mayo Clinic in Rochester, MI, explains, “TDP-43 is now one of the proteins that need to be targeted as [a] potential treatment of Alzheimer’s [a neurodegenerative condition].”

“I don’t think we’ll be able to cure [Alzheimer’s] without addressing TDP-43,” he adds.

The research appears in the Journal of Cell Biology.

Of mice and men

The researchers carried out the initial study using mice. The results suggest that in the absence of TDP-43, oligodendrocytes lack the enzymes to synthesize cholesterol adequately. Additionally, they revealed that supplementary pathways supplying the oligodendrocytes with cholesterol might also be blocked.

Furthermore, the study shows a reduction in the levels of low-density lipoprotein receptor (LDLR) and very-low-density lipoprotein receptor (VLDLR) in TDP-43 deficient cells. Both of these receptors are responsible for taking cholesterol from the blood into the cell.

This finding supports the hypothesis that both cholesterol biosynthesis and uptake are disrupted in TDP-43-deficient oligodendrocytes.

In collaboration with Prof. Edward Lee at the University of Pennsylvania in Philadelphia, the team extended the study to human patients. The results reveal that reduced cholesterol metabolism appears to occur in people with frontotemporal dementia with TDP-43 pathologies in oligodendrocytes.

Interestingly, the study also suggests that supplementing the TDP-43 deficient cells with cholesterol restores their ability to maintain the myelin sheath.

Ling explained to MNT that the primary limitation of the study is that the initial work took place in mice. “More studies and replications are needed to confirm [our] findings, including in patients with [amyotrophic lateral sclerosis] and other neurodegenerative diseases with TDP-43 pathologies,” he added.

What does the future hold? 

It is still early days for the results from this study, but they hint at interesting areas of research that might open up in the future.

Ling told MNT that he is now very interested in cholesterol metabolism and the central nervous system (CNS) because the regulation of this process in the CNS follows similar mechanisms that scientists have already discovered but with a unique twist.

For Ling, investigating such twists is a fascinating area of further study. He is hopeful that in a few years, he will have something new to report.

As more research investigates the link between cholesterol and the CNS, perhaps one day, cholesterol regulation will become part of the therapeutic regimen for treating neurodegenerative diseases. Or, perhaps not. Only time will tell.

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