Scientists have uncovered the mechanism of disruption of the membranes of neurons in the APOE4 variant
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- Scientists have uncovered the mechanism of disruption of the membranes of neurons in the APOE4 variant
Scientists at the Massachusetts Institute of Technology have established how APOE4, a gene variant associated with an increased risk of late—onset Alzheimer's disease, disrupts the formation of myelin, the lining of nerve fibers. In laboratory experiments, the effect on the discovered mechanism made it possible to improve this process. Why the brain needs such "isolation", why fats can accumulate inside cells, and what the discovery means for finding a cure — in the Izvestia article.
Why do neurons need "isolation"
To remember a familiar face, read a sentence, or find your way home, the brain needs to transmit signals between nerve cells. Some of these signals travel along the axons, the long outgrowths of neurons.
Many axons are surrounded by myelin. This sheath is often compared to the insulation of an electric wire: it helps the nerve impulse to spread quickly and efficiently. However, myelin is a living structure that is created and maintained by special cells.
Therefore, the state of neural connections also depends on how well neighboring cells are doing their job. If myelin formation is disrupted, it can impair signal transmission.
In the new work, the researchers focused specifically on oligodendrocytes and found a malfunction in the use of lipids. In cells with APOE4, they accumulated in the form of droplets, while the formation of the myelin sheath was disrupted.
Why is APOE4 attracting so much attention
APOE is a gene that contains instructions for the production of the protein apolipoprotein E, which is involved in lipid transfer. This gene has several common variants, including APOE2, APOE3, and APOE4.
But the presence of APOE4 is not equivalent to a diagnosis. As the US National Library of Medicine explains, a person inherits an increased likelihood of the disease, rather than the inevitability of its development. Not all APOE4 carriers develop Alzheimer's disease, and not all sufferers have this variant.
It is important for researchers to understand how a genetic trait changes the way cells work. The very knowledge of the increased risk does not yet explain exactly where the violation occurs and which process can be affected.
The new work continues the research of this group. Back in 2022, scientists showed that APOE4 is associated with the accumulation of lipids in oligodendrocytes and a violation of myelination — the formation of myelin. Now they have tried to find out what molecular mechanism is behind this malfunction.
There are fats, but the shell is formed worse
At first glance, the situation looks paradoxical: lipids are needed to create myelin, but their accumulation inside the cell is accompanied by a deterioration in the formation of the membrane. The explanation is that the presence of a substance and its proper use are two different things. The cell needs to regulate the metabolism of lipids, their storage and direction for specific tasks. An excess of fat droplets does not mean that the material is successfully used for myelination.
Scientists have linked the detected disorder to a weakening of the Wnt signaling pathway. This is the name given to the system of molecular interactions by which a cell regulates certain processes and the activity of genes.
This is a different type of signal than the electrical impulses of neurons. In this case, we are talking about the biochemical regulation inside the cells that create myelin. In the studied oligodendrocytes with APOE4, the activity of this pathway was reduced. When the researchers were able to restore the appropriate signaling, the number of lipid droplets decreased and myelin formation improved.
Thus, the work concerns one's own metabolism in brain cells. She did not check whether changing the amount of fat in the diet could correct the detected disorder.
How to search for the cause of the crash
The team was led by MIT Professor Li-Hui Tsai, and the lead author of the study was Leila Akai. To find the mechanism, the scientists used several methods. One of them is genome—wide CRISPR screening. In human oligodendrocyte cultures with APOE4, the researchers systematically disabled individual protein-coding genes and checked how this affected the accumulation of lipid droplets.
In simple words, scientists have consistently checked which elements of the cellular system affect the problem. Such a search allows us to go beyond the limits of a pre-selected hypothesis: a potentially significant gene may turn out to be a gene whose role the researchers did not initially suspect.
It is important that gene editing was a tool for cell research here. Scientists have not performed gene therapy in humans and have not corrected APOE4 in patients. In parallel, they investigated the availability of DNA sites. In a cell, DNA is packed together with proteins, and different parts of it can be more or less readable. It depends on how easily the cell can use the instructions contained there.
The ATAC-seq method helped to compare this availability in samples with APOE4 and APOE3. Human cell cultures and postmortem brain samples were used for analysis. The genes supporting Wnt signaling were found to be less accessible in samples with APOE4.
"There was a striking coincidence between the results of ATAC-seq and CRISPR screening. Both methods indicated a dysregulation of the Wnt signaling pathway," Tsai noted.
The coincidence of the results of different methods made this path especially interesting for further verification.
How did myelin formation improve?
The next stage was devoted to two participants of the Wnt system, beta—catenin and the enzyme GSK3b. In the studied mechanism, the first supports signal transmission, and the second helps to suppress it.
The researchers found less beta-catenin and more GSK3b in oligodendrocytes with APOE4 compared to cells with APOE3. This provided a direction for the experiment: to check whether the lipid metabolism would change if the work of GSK3b was slowed down.
The research compound CHIR99021 was used for this purpose. In cell cultures with APOE4, it reduced the accumulation of lipid droplets. Then the scientists moved on to more complex models — three-dimensional organoids containing neurons and oligodendrocytes. Such structures allow us to observe the interaction of different cells, although they do not reproduce a full-fledged human brain.
In these models, suppression of GSK3b improved myelin formation and promoted axonal growth. The researchers obtained a result concerning both the accumulation of lipids and the formation of nerve fiber sheaths.
An additional experiment showed a change in the opposite direction: exposure enhancing the activity of GSK3b in cells with APOE3 increased the number of lipid droplets. This reinforced the conclusion about the role of this mechanism.
What experiments on mice have shown
After cellular experiments, the approach was tested in mice with the human variant of APOE4 and genetically modeled tau pathology. This is the name given to disorders associated with the tau protein, changes in which are characteristic of Alzheimer's disease.
The animals received CHIR99021. Compared to the control group, they were found to have fewer lipid droplets in the hippocampus, an area of the brain important for memory formation. Myelination in this area was also more pronounced.
Animal testing is important because a single cell culture does not reproduce all the conditions of a living organism. However, the mouse model reflects certain features of the disease, rather than the entire human Alzheimer's disease.
Reducing the number of lipid droplets and improving myelination are specific experimental results. They cannot automatically conclude that people will recover their memory or stop developing dementia.
Why is this not a ready-made treatment yet
The study suggests a potential target for therapy development: disruption of Wnt signaling and related GSK3b activity. However, there are still several fundamental issues between successful laboratory exposure and the drug for patients.
It is necessary to check the safety of the intervention, the appropriate method of delivery of the substance and the possibility of long-term use. A separate task is to determine whether the improvement of myelination will lead to significant results for the patient: the preservation of memory, independence and everyday skills. Compound CHIR99021 was used as an experimental instrument in this work. The data obtained is not a basis for its independent application.
It is also important that Alzheimer's disease affects many interrelated processes. Among its characteristic features are the accumulation of beta—amyloid, changes in the tau protein, disruptions in the functioning of cells and the connections between them. The discovery of one mechanism does not mean that it explains all the manifestations of the disease.
But such a result allows us to formulate the following research task more precisely. Scientists have the opportunity to test whether it is possible to improve the functioning of cells supporting nerve fibers through a specific molecular pathway.
The authors intend to study in more detail how the loss of Wnt activity alters lipid metabolism, as well as the relationship of GSK3b with changes in tau protein. Akai and Tsai have filed a patent application based on the results of CRISPR screening. The very fact of the application does not confirm the effectiveness of future treatment: it will have to be evaluated separately.
The new work adds to the understanding of Alzheimer's disease: in order to preserve neural connections, the condition of the neurons themselves and the cells that create the myelin sheath for them is important. It was the disruption of this collaborative work that became the subject of an experiment and a possible direction for further therapy search.
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