APOE4 fixed
The key mechanism of the development of Alzheimer's disease has been neutralized
Anna Kerman, XX2 century, based on Medical News Today – Breakthrough: Researchers fix Alzheimer's gene
For the first time, scientists have managed to find out exactly how the most well-known genetic risk factor for Alzheimer's disease causes the development of the disease. Moreover, the researchers were able to "fix" this gene and "erase" its pathogenic manifestations.
The role of the apolipoprotein E (APOE) gene in the development of Alzheimer's disease is now being studied extremely intensively. Scientists, for example, already know that having one copy of the APOE4 variant increases the risk of disease by 2-3 times, and two copies – by 12 times.
Normally, the APOE gene controls the synthesis of a protein with the same name. Then the resulting protein combines with fats to form lipoproteins. The latter, in turn, help to transport cholesterol through the circulatory system and control its level.
However, the genetic variant of APOE4 is dangerous for the brain. Several studies have shown that it increases the risk of formation of toxic amyloid proteins and toxic tau protein.
A group of scientists from the Gladstone Institutes in San Francisco decided to find out exactly how the genetic variant APOE4 is involved in the development of Alzheimer's disease. The results of the work are published in the publication Nature Medicine.
APOE4 was first studied in human cells
The researchers wondered what is the small but critical difference between the genetic variants APOE3 and APOE4. Does the protein synthesized with the participation of APOE4 lose its functions? Or is it that relatively large amounts of APOE4 have a toxic effect?
According to the lead author of the work, Dr. Yadong Huang, professor of neurology and pathology at the University of California at San Francisco (University of California, San Francisco), the search for answers to these questions is extremely important: "This is important in fundamental terms," explains the professor, "because it affects the approach to treatment. If the damage is caused by impaired functioning of the protein, it is possible to increase the level of the latter in order to restore normal functioning.
But if the accumulation of protein leads to a toxic effect, the production of such a protein should be stopped in order to protect the body from its destructive effects."
As part of the new work, scientists have modeled the disease in human cell culture, for the first time studying the effect of APOE4 on human brain cells.
Dr. Huang explains why changing the model itself was a huge step towards Alzheimer's research: "Many drugs work great on model mice, and then fail in clinical trials. How poorly the mouse model reproduces the disease in humans raises a number of concerns."
In mice and humans: the study demonstrated differences
By applying stem cell technology to the skin cells of Alzheimer's patients who carried two copies of the APOE4 gene, Dr. Huang and his colleagues created neurons. Similar manipulations were carried out with skin cells of healthy people-carriers of two copies of the APOE3 gene.
Scientists have discovered that the APOE4 protein has a "pathogenic structure" in human brain cells. This means that the abnormal form of the protein prevents it from functioning normally, which leads to a series of problems that cause the disease.
It is very important that the researchers also described the following observation: "APOE4 increases the production of [beta-amyloid] in human, but not in mouse neurons."
There is no activation of beta-amyloid synthesis in mouse neurons, and this may explain the inconsistencies in the effectiveness of the same drugs administered to humans and mice. This information is extremely important for the future development of drugs.
Correcting the "broken"
At the next stage of the work, Dr. Huang and his colleagues decided to find out whether the disease is caused by the loss of APOE3 protein or the accumulation of APOE4 protein.
To do this, the researchers compared neurons that did not produce either APOE3 or APOE4 with cells into which APOE4 was injected. The former continued to function normally, while the addition of APOE4 led to the appearance of disorders characteristic of Alzheimer's disease. This experiment confirmed the hypothesis that the presence of the APOE4 protein is the cause of the development of the disease.
At the last stage of the study, scientists began to look for a way to "fix" APOE4. To do this, the researchers used a previously developed "structural corrector" that makes APOE4 look like APOE3. The introduction of a "corrector" into neurons with the APOE4 gene corrected defects, destroyed signs of the disease, restored the normal functioning of cells and helped neurons to live longer.
The small molecule apoE4SC disrupts the ionic interaction between Arg-61 and Glu-255. This converts ApoE4 into an apoE3-like molecule both structurally and functionally. Figure from the article Mahley and Huang Small-molecule Structure Correctors Target Abnormal Protein Structure and Function: The Structure Corrector Rescue of Apolipoprotein E4–associated Neuropathology (J Med Chem. 2012) – VM.
Perhaps in the future this approach will be used to treat patients with Alzheimer's disease who are carriers of the APOE4 gene.
Portal "Eternal youth" http://vechnayamolodost.ru