How cholesterol promotes cognitive decline and neurodegenerative diseases

Is there a connection between cholesterol metabolism and brain health? It would seem so. A recent study examined the link between neurodegenerative disease proteins and defective cholesterol metabolism. The results indicate that defective cholesterol metabolism is a common feature of people with neurodegenerative diseases. The researchers suggest that restoring cholesterol levels could become a new beneficial strategy in the treatment of certain neurodegenerative diseases. This study was published in the Journal of Cell Biology.

Cholesterol, an essential component of the body, helps maintain the integrity of cell membranes. It also contributes to the synthesis of hormones, vitamin D and other important cellular substances. In the body, about 23-25% of total cholesterol is found in brain cells. There, it helps enrich the myelin sheath, which covers nerve cells and plays an important role in the conduction and transmission of nerve signals. This transmission is necessary for the coordination of bodily functions, such as walking and speaking. Damage to the myelin sheath can slow or reduce transmissions, leading to neurological problems. Recently, researchers have set out to investigate why specific neurodegenerative diseases lead to the loss of cholesterol-rich protective myelin sheaths.

Cognitive decline, neurodegenerative diseases and cholesterol: the confirmed link

Researchers from the 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 the protective myelin sheaths. Their research reveals that the protein TDP-43, which is implicated in pathologies such as amyotrophic lateral sclerosis and frontotemporal dementia, influences cholesterol metabolism in the brain. It also showed that the synthesis and absorption of cholesterol play an essential role in the formation of the myelin sheath.

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Professor Shuo-Chien Ling, one of the study’s authors, explained why he decided to study the links between TDP-43 and cholesterol metabolism:
“We investigated the link between TDP-43 and cholesterol metabolism based on experimental data we obtained from our previous work in mice that had TDP-43 deleted from oligodendrocytes. » Oligodendrocytes protect and myelinate neurons, thereby improving transmission speed. Specifically, we found that mice whose oligodendrocytes lack TDP-43 develop progressive neurological phenotypes leading to early lethality. These phenotypes are accompanied by the death of oligodendrocytes and a progressive loss of myelin,” he added. An imbalance in cholesterol regulation is a common feature associated with neurodegenerative conditions, such as Alzheimer’s disease and Parkinson’s disease.

In mice as in humans

The researchers performed the initial study on mice. The results suggest that in the absence of TDP-43, oligodendrocytes lack the necessary enzymes to synthesize cholesterol adequately. Moreover, they reveal that additional pathways supplying oligodendrocytes with cholesterol could also be blocked.
In addition, the study shows reduced levels of low-density lipoprotein receptor (LDLR) and very low-density lipoprotein receptor (VLDLR) in TDP-43-deficient cells. These two receptors are responsible for moving cholesterol from the blood into the cell.

This finding supports the hypothesis that cholesterol biosynthesis and absorption are both impaired in TDP-43-deficient oligodendrocytes.
Working with Professor Edward Lee of the University of Pennsylvania in Philadelphia, the team extended the study to human patients. The results reveal that a reduction in cholesterol metabolism appears to occur in people with frontotemporal dementia with TDP-43 pathologies in oligodendrocytes.

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

What does the future hold?

The results of this study are still in their infancy, but they point to interesting areas of research that may open up in the future.
The study of these peculiarities is a fascinating field of study. As research grows on the link between cholesterol and cognitive decline, perhaps one day cholesterol regulation will be part of the therapeutic regimen for treating neurodegenerative diseases.

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TDP-43 mediates SREBF2-regulated gene expression required for oligodendrocyte myelination


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