Study of Alzheimer's disease (2)
Genetic mechanisms of Alzheimer's disease
Evgeny Rogaev, Post-science
Alzheimer's disease can affect people of completely different ages, but it is more common in age groups older than 60-65 years. Especially often the disease occurs in a group of people over 80 years old. There are rare cases of detection of the disease in people under 60 and even up to 40 years old. Scientists didn't know if they were different diseases or the same one. Now a consensus has been reached: we believe that this is the same disease, but in early and late forms, having the same signs: histopathological, amyloid plaques, neurofibrillary tangles.
Before genetic studies, we did not know why some people develop the disease earlier and others later, so many works were devoted to epidemiological factors. Scientists have studied what environmental factors can influence the development of the disease. The most important factor is aging. Previously, there was a popular idea that some metals, such as aluminum, are a negative factor affecting Alzheimer's disease. The incidence of Alzheimer's disease was higher where high aluminum content in water was found. These numerous epidemiological factors, which scientists pointed out in their works, were often not confirmed in other studies.
Summing up the confirmed data, we can identify two main risk factors: head injury and sleep deprivation. Head trauma is an additional risk factor for the development of various forms of dementia, including Alzheimer's disease, especially if it is combined with some genetic factors, which we will talk about later. People who are constantly exposed to different types of insomnia are at increased risk.
I emphasize that scientists are trying to figure out whether this is a methodical artifact or really the cause. After all, the opposite situation is also possible: patients who have the initial stage of Alzheimer's disease suffer from insomnia. However, an experiment on mice showed that the level of beta-peptide increases in animals that were artificially forced to stay awake. It is found in amyloid plaques and is a risk factor for the development of the disease.
The third factor affecting the development of the disease is the presence of episodes of loss of consciousness in a person's life, including during surgical operations. These are moderate risk factors that are incomparable with factors such as age and genetics. The search for external factors gives us little information about the mechanism of the disease. Let's move on to genetic research now.
In the 1940s, scientists described cases of early forms of Alzheimer's disease appearing in families that develop before the age of 60. For the late form of the disease, such a strict trend was not observed. It is quite difficult to study such patterns, because relatives could not live up to the age of the disease.
The study of Alzheimer's disease is an example of the successful application of various research methods to identify different genes of the disease. Scientists use the search for the disease gene through a biochemical product. We know the disorder at the level of protein or biochemistry and on this basis we are trying to find the gene we need. We know that there is an amyloid plaque or peptides, and we believe that this is not just a marker of pathology, but its cause. This is how the amino acid sequence of the peptide – 42 amino acids - was first deciphered. With the help of this information, a nucleotide sequence of DNA was derived, which should encode a protein with a violation. Scientists have managed to isolate the amyloid precursor gene. It turned out that the pathogenic peptide affecting the development of Alzheimer's disease is only a small piece of the amyloid precursor.
Since we are considering a genetic disease, we are dealing with mutations. Scientists began to look for mutations of the amyloid precursor in families with an early form of the disease and were able to detect them. The mutations were located near a piece that is associated with Alzheimer's disease. However, when more than 90% of the remaining families began to look, no mutations were found. Then we started research with an international group of those families in which there was no mutation in the amyloid precursor gene.
We used a completely different technology, very complex and time-consuming. It allowed us to identify a gene about which we know nothing: neither functions nor biochemical products. This technology is called the positional gene cloning methodology. It lies in the fact that if we know the markers – polymorphic DNA scattered throughout the genome – then we need to accumulate them so that we can trace how each of these markers is inherited in families. If it is inherited along with the disease, the gene is somewhere nearby. We know the localization of markers on chromosomes and can first find the localization of the gene, and then pull out the gene itself. This was done even before the human genome was decoded.
In this way, we managed to find a gene that we called "presenilin-1" – pre-aging. It turned out that this gene encodes a protein with multiple transmembrane domains. It is he who sits in the cell membrane, penetrating it several times. Nothing was known about this gene. A lot of work has been done over a decade and a half to study the function of this protein and gene. It turned out that this protein is an unusual enzyme that cuts the amyloid precursor inside the membrane in which it sits. As a result, the peptide falls out. Another protease is also used, another enzyme that cuts the membrane from the outside. Mutations were found in presenilin-1. Then a homologue was isolated – a similar gene presenilin-2. These mutations enhance cleavage.
As a result, we now know the mechanism for all forms of Alzheimer's disease. This is the mechanism of proteolysis, that is, the improper cleavage of proteins inside membranes. Even if there is no mutation, splitting still occurs, but not at this rate. If we know the targets, we can develop a drug. This explains most of the very early forms of Alzheimer's disease, there are no such mutations for the later forms.
Why then does the disease occur? A different genetic approach was applied: the genes known in the mid-1990s were simply sorted out. It was accidentally discovered that the well-known apolipoprotein E-gene, which is involved in the transport of lipids, affects Alzheimer's disease. In the human population, it is represented in three types: e2, e3, e4. In Europeans, e4 occurs in 10% of cases. It turned out that this gene variant is a strong risk factor for the development of Alzheimer's disease, including late forms. If this option comes from dad and mom, you have two copies of the e4 gene, the risk of the disease is 10 times higher. We have explained another 40% of cases of Alzheimer's disease, but still cannot explain about 40-50% of cases that are related to other factors. One way or another, we understood the genetic component of Alzheimer's disease. We do not fully understand the molecular mechanism of how the apolipoprotein gene works, but most likely it also acts on the mechanism of proteolysis. Now we can use this for molecular diagnostics. If we find a mutation in presenilins for a congenital disease in very young children, we can accurately predict the development of the disease before the age of 60-65. But, unlike breast cancer, we cannot resort to any surgical preventive operations. Cases of preimplantation testing using Alzheimer's disease gene analysis have been described. At the request of a woman, her oocytes were tested, and one that does not carry a gene with a mutation was selected. Artificial insemination was carried out only by cells that do not carry mutations. This method generates certain ethical questions that lead to all kinds of discussions, because this is not a congenital disease – it occurs after 40 years.
Unfortunately, clinical trials of drugs aimed at the primary mechanism have not yet led to real results. When we try to influence the mechanism that we predicted, it is not always possible to see a positive result immediately. Although in animal models, in particular mice, it was possible to carry out a process called "immunization": the addition of a beta-peptide and the appearance of an antibody to this peptide. On the model of Alzheimer's disease in mice, the resorption of amyloid plaques in the brain was achieved. Testing the method on humans has led to a number of negative effects. The main one is inflammation of the brain, the emergence of a strong immune response. This area has not been closed yet, scientists are conducting research with safe vaccination and other forms of peptides.
There is a development of humanized human antibodies. Scientists receive antibodies and use them to try to treat patients. But recent clinical trials have shown that there are no positive results and no improvement in the cognitive properties of patients. We know the primary mechanism, but we don't have the drugs. The same drugs that affect the neurotransmitter acetylcholine are still used. Acetylcholine esterase inhibitor is an enzyme that destroys acetylcholine, a neurotransmitter between neurons that transmits signals. If it is kept between cells, cognitive abilities will be better. But this preservation does not last long, it is a symptomatic treatment that does not eliminate the very mechanism of the disease. Now many pharmaceutical companies refuse to develop drugs that act on the primary mechanism – amyloids. They are betting on the development of new approaches.
One of the approaches that we are interested in is the use of small RNA interfering molecules that can bind directly at the RNA level to targets in Alzheimer's disease. We are interested in the apolipoprotein E-gene. In a collaborative group with scientists from the University of Massachusetts, we are investigating whether a small RNA molecule can suppress activity at the level of the apolipoprotein E-gene. We want to see an improvement in mouse models. If we go back to aging, the next stage for us is an attempt to find those risk factors that cause aging. We are interested in epigenetic changes – chemical modifications of the genome that affect the activity of genes. Such changes occur in neurons during aging. We don't know if they can be influenced to reverse such changes. Epigenetic changes, unlike mutations, can be reversed, thereby changing the regulation of genes. We carry out such work in order to see the signals of gene activity in neurons that occur or change with aging. These genes may be new targets for treatment.
About the author:
Evgeny Rogaev – Doctor of Biological Sciences, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Evolutionary Genomics of the N. I. Vavilov Institute of General Genetics, Head of the Department of Genetics of the Faculty of Biology of Moscow State University, University of Massachusetts Medical School.
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