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To cure Alzheimer's, we must forget what we know so far

At first a tree goes down. No one notices the memory in a dense and elegant forest. Then another tree falls, and another one, and many trees collapse. Some rhetorical memories appear, the meanings that are within them are left behind. The forest is cleared. Here's a neck neck. Who are you? My son Nice to meet you Who are you?

5.7 million Americans live with Alzheimer's disease; 5.7 million people who are exhausting their minds, when memories are becoming dirty, their identities disappear. The number of Israel is 150,000. Life expectancy increases with the increase in the number affected: from 2050, 13.8 million Americans will suffer from Alzheimer's disease. Emotional charge can not be endured. The economic burden is very large. For decades, scientists from around the world have been investigating the disease, investing billions of dollars in research, to show nothing. Without treatment, without medication, without relief. The only accepted drug for use is the only symptom of the disease that affects only a few illnesses.

Sometimes there is a media report in a progressive, hopeful, or successful experimental mouse experiment, but in the end, the expectations disappear. Now, after failing more than 400 experiments around the world, some early stages, while other human-induced testing and illness-centered development centers closed their Alzheimer's disease, the issues begin to worsen. Is there a wrong direction of investigation from the beginning? Is not it a single theory to explain everything wrong? Most scientists continue to advocate conventional theory and explain individual failure of experimentation; However, many times, the fields have stopped and the paradigm shift is essential.

Alzheimer's disease is the most common cause of dementia, that is, a significant decrease in cognitive functioning. Possible causes of other dementia include: vitamin deficiency, depression and medication reaction, among others. This disease is gradually developing. Initially, short-term memory has been damaged, long-term memory, and over time, other cognitive functions, such as orientation in time and space, ability to plan and others. In the following stages, the engine is also reduced. All of these functional changes are statements Physical changes in the brain, responsible for the creation of new memories in the first hippocampus, then in complementary regions. Gradually and gradually, the nervous cells deteriorate and degenerate and the brain gradually decreases.

There are two types of Alzheimer's known. Hereditary and rare (it causes a small part of the patients). It begins at early age (ages 30 to 40), and a dozen genes have been identified. The second reason, which appears in advanced age, is not so clear, so they are called "random." du Random Alzheimer's It also has a genetic component With this kind of illness, the fundamental importance lies in the individual's lifestyle.

The research has undergone almost 30 years of dominant hypothesis called a protein called a finger amyloid beta, the main cause of the disease that accumulates in the brain. It occurs with the nerve cells and creates plaques between them, interrupting neuronal communication and weakening the nervous cells by the loss of cognitive abilities. The amyloid brain plaque has an Alzheimer's disease and distinguishes it from other dementia diseases. The "Amyloid Hypothesis" began to develop from a longer protein, and then found that more than 150 mutations that appear in hereditary Alzheimer's disease are involved in the process.

This hypothesis finds two major difficulties. first, There is no correlation between the cognitive plaque and the cognitive abilities. Many people have amyloid plaque in the brain, but they are cognitively healthy. Secondly, hundreds of treatments for reducing or removing plates in the brain of the patients were not recovered or at least reduced the loss of cognitive abilities. However, the amyloid hypothesis was retained.

Over time, researchers found the involvement of other proteins, tauBefore the death, it spills nervous cells. The hypothesis was updated as follows: the amyloid plaque started the process and the knots tau they conclude. Patients were not healed, either tau It was damaged, it could undo the hypothesis of its major situations. Why is this

Although there is a growing number of difficulties, scientists only think of a minority to think differently about the patient. Many of them accept this It is difficult to say that their studies are published and criticized, and worse, they have been excluded. Two years ago, for example, 33 scientists and PhDs published an article arguing that hundreds of findings have been published in the years they say. The connection between bacteria and viruses, and Alzheimer's disease. These findings are not just a circular link, for example, they suggest People suffering from herpes may have an increased risk of Alzheimer's disease, but it is a real cause: parasites participate directly in the development of the disease.

When the cells are infected with herpes or the brain of the red mouse infects salmonella, they form an amyloid plaque; In the brain of people who have died of Alzheimer's disease, herpes DNA is found specifically where amyloid plates are present; and so on. Such a discovery led to a hypothesis The natural role of the amyloid is to protect against cells against parasites, only when this problem occurs when this task fails. The solution, according to this approach, is ridiculously simple: antibiotics or antiviral drugs to eliminate parasites. In fact, the approach proposals say that people treated with antiviral drugs are 10 times less Alzheimer's. Imagine that.

However, the image is probably harder. Alzheimer's, like cancer, apparently is not the disease. Its causes may be diverse, so medications and solutions must also be diversified and coordinated, depending on the cause and status. There is a need for a combination of many factors in Alzheimer's development. As a result, it is important for scientists to start developing newer avenues and looking at different angles.

Among the supporters of the change are two Israeli researchers: Inna Slutsky from the University of Tel Aviv and Michal Schwartz Weizmann Institute of Sciences at Rehovot. Each one starts from the starting points and proposes new ideas to allow freedom to stop that condition.

Inna Slutsky.
Inna Slutsky. "I think it's easier to ask the mice worse than guilt." It's not easy to admit that the approach was a mistake. "Credit: Meged Gozny

Crushing of the brain

Professor Slutsky, at the School of Psychology and School of Neolithic Sciences at TAU, conceptual ideas are difficult to eradicate, especially after some of these resources.

"Scientists who adhere to a hypothesis, of course, have difficulty explaining," he says smiling. "Until recently, brain amyloid plaques can only be found in an autopsy. Alzheimer's has been developing for 15 to 20 years until it reveals cognitive development, scientists say, the autopsy also creates plaque in people who do not develop symptoms. If they were developed.

"On the contrary," he continues, "people with cognitive illnesses that diagnose Alzheimer's disease, already in the middle of the disease, have started creating 15-year-old amyloid plaques, and the damage to the brain during the years is too high, so the dish does not work."

The door closes after the horse comes home. Too late

Slutsky: "Yes, that is the argument, which is why the amyloid is definitely a definitive target and is worthy of parasitism developed in its dishes, but the diagnosis should be done much earlier, when the individual is 50 years old, for example, before the appearance of Alzheimer's dementia signs . Today, amyloids enable imagery technologies that detect the life of a person, so that such plates begin to treat people before they show signs of dementia. and before you destroy your nerve cells".

But will the drug continue to be treated, does Alzheimer's have?

"Other people claim claims, because the mouse is not enough for the model. I think it's easier for mice to ask worse than guilt. It's not easy to accept it's a mistake. It is not unreasonable to say that the amyloid is the only cause of the disease. In fact, hereditary Alzheimer's disease, which contains mutagenic genes that cause amyloid production, develops at least 30 to 40 years.. The development of the amyloid is therefore just another product that is interrupted in the brain. For this reason, the approach that leads to the elimination of amyloid plaques does not seek the solution. "

Slutsky began to investigate Alzheimer's disease after being investigated, encoded and conserved by the nerve cells after investigating the information. "When I got into Alzheimer's disease," he says, "and I started reading articles, unfortunately, I was there for each article that presented a specific result, the other one appeared the opposite. In innocuous ways, I thought if I wanted to understand the Alzheimer's disease, the depth of memory mechanisms We need to understand and then analyze how they cause the disease, but that was not the focus, at that time, Most researchers were the result of biochemistry, pathology and genetics and were immediately known as the pathology of the disease. From biochemical perspective all amyloid beta aspects were analyzed: its structure, the characteristics of the plates that it generates and how they are produced. In general, all the mutations related to hereditary disease have been found and mutations that increase the risk of Alzheimer's risk are also found.

"What surprised me is to analyze the brain as an organ like any other, like the liver, for example: it becomes pure and looks at how protein works and their genes are in charge. Over the years, no one has a distinctive role in the brain's transmission of electrical signals. I was surprised to find that the electrophysiological methods were not in the study of Alzheimer's, as in other neurological diseases. Can not you get an epilepsy or Parkinson's on the brain without analyzing the brain's electrical signals? In some ways, Alzheimer's has lost standard research on neuronal networks.

"Over the past 50 years, there has been tremendous progress in the memory analysis, we know how to produce short and long memories, they are stored, etc. However, as regards the illness that has a difficult problem, all these ideas have been ruled out. In my opinion, When basic sciences show that they depend on the electrical activity of the neural network, we must be able to identify and treat the simple nature of Alzheimer's.".

So now you have to go back to the drawing and start from the beginning?

"No, we need to open our opinions and ask ourselves more questions. Research focused on biochemical fields has not worked, this vision has to be abandoned and a new era has been launched. From my point of view, proteins are in nerve cells to allow their electrical activity. When we knew the normal function of the amyloid brain, we understood what memory memory is the first time. "

Previously, the physiological function of the known amyloid beta was unknown?

"In general, hippocampus has a regular transmission of electrical signals to create the memory and preservation of the plasticity of the nervous cells, which is why the amyloid cell is at a certain level, not only at a high level but also a serious problem with Alzheimer's disease but also a low level of communication it is interrupted. "

A laboratory mouse.
A laboratory mouse. "I think it's easier than asking the mice to be worse than guilt," says Inna Slutsky. Credit: NATACHA PISARENKO / P ASSOCIATED

Then, Slutsky's amyloid causes ordinary electricity activity in a healthy brain, and, surprisingly, the opposite is also true: normal brain activity affects amyloid production. Amyloid is transformed into two forms, short and long. The second is a problem. A long amyloid is the "bad" that accumulates and produces the plate; The "short" type is "good" and they are balanced. Most mutations that cause hereditary Alzheimer's help to produce long amyloid and "bad" ones.

"When we measure the activity of a healthy hamster," said Slutsky, "when we see the high rate of electrical activity, there is a" bad "learning and memory creation and amyloid mass.

Learning new things (language, a new knowledge area …) Is it a recommendation to prevent Alzheimers? Why do we encourage the development of electrical activity by learning and memory, promoting "good" amyloid production and inhibiting "bad"?

"I do not have a simple answer to that question. I can only say that in the coming years we can find some good" brain "models of the brain and how we can understand how to maintain learning, nutrition or physical activity, which has been published in recent years by people with" mild cognitive impairment " . [MCI]A condition seen as a previous stage of Alzheimer's disease. When electrical pathology was treated, he improved his memories. Of course, I found it very exciting. "

In the case of Slutsky, the key concept is "homeostasis", which changes in diseases like Alzheimer's disease. Homeostasis life is the basic principle and maintains a stable internal environment, as well as changes in the external environment. Blood pressure, salt levels and body temperature remain in the body, which are fairly stable, and their interruption or deviation activates mechanisms to restore the stable system. The classic example of this mechanism in the human body is the secretion of insulin after eating, since the sugar levels remain within the normal range. The analogy of the technology would be an objective value that would be objective, such as 24 degrees (75 degrees). When the temperature in the room is diverted to that value, it receives the order of cooling or heating of the air conditioner and returns the desired temperature value.

A healthy brain works the same way, says Slutsky. He performed a measure of electrical activity of a rat brain in well-known experiments, one of the eyes of a rat was closed and, as expected, the electrical activity of the electric region of sight fell. Surprisingly, however, Two days later, the region's electricity activity returned to its original level, even though the eye was closed. In other words, the system recovered even after the shock.

"We also show a similar recovery in the hipocampus nerve cell network," says Slutsky. "This means that the neuron network has mechanisms for its electrical stability, as well as dramatic changes. Stability is one of the basic features of healthy brain and is, in fact, a condition for health."

You speak about stability, but it is an organ that responds to the brain's circumstances.

"This is the point: there is a game between two forces: change and stability, the ability to adapt to the environment and the creation and protection of memories, depending on the flexibility of the neural network, the risk of a malfunction of the system due to the tendency of instability and therefore the development of the brain to develop domesticostasis mechanisms.

"Our hypothesis," he continues, "a homeostatic control circuit associated with Alzheimer's, memory and study is interrupted. Our previous results suggest that the genes involved in Alzheimer's disease are related to this control, for example, a protein involved in the determination of the objective value of the hippocampus We have found that the value of this system depends on a certain rate of electric activity. "If this value is not interrupted, the system deviates from an abnormal state that damages plastic and memory, and we are looking for a way to recover the value of its original state."

The scientific world, aimed at pathologic electrical brain-brain manifestations in the world of Alzheimer's patients, has recently released some interesting discoveries. For example, dozens of randomized Alzheimer's patients show a track record of electric brain activity 40 percent of them had seizures in dormant epilepsy. In addition, the cognitive situation of those who suffered attacks worsened faster than people who were not alive. In other words, there is a connection between electrical pathology and damaged memory.

Recently, this irregular electric activity was created It also appears in the brain of the people of the manifestation of the disease (Those that started to show signs of depression after Alzheimer's disease). If so, it exists the possibility of initial identification of the disease, the appearance of difficult memory loss symptoms and the creation of amyloid plaques.

Slutsky has similar thoughts. "From our point of view, the main cause of Alzheimer's disease or, at least, one of the main causes of cerebral homeostatic control is unstable, we want to develop a method of early diagnosis of the disease, which is a serious shake of the brain and then measured to the extent that the system returns its previous condition. The time to return to the equilibrium point can be a good indicator of brain health and therefore serves as an instrument for early diagnosis of Alzheimer's disease. "

Is not it a traumatic test?

"Yes, but it would be short: the beginning of the diagnosis session for the diabetes, the patient receives a large amount of sugars, which is particularly harmful, how it is managed and how long it takes to return to its normal balance. To understand the basic mechanisms of memory and homeostasis.

"When you use basic science, you can not fail. Go to the right, you will find something interesting: go to the left, you'll find something in it, it does not bother with the situation you want to find a drug, and there will always be bias. , it will be fine if my theory about the development of the disease is proven to be incorrect. Negative responses, when connected to the ground, also lead us to the solution. The critical thing is not imprisoned by a convention. "

Michal Schwartz
Michal Schwartz "The immune system is an illness capable of facilitating Alzheimer's disease, which is the direction we follow. In a sense, we are rejuvenating the brain." Credit: Ofer Vaknin

Border control barrier

A definitive resignation from a scientist is the Michal Schwartz convention in the Weizmann Institute's neurology section. Professor Schwartz was one of the most prestigious magazines Natural Medicine He has recently been asked to try to penetrate the confusing network of Alzheimer's education. He also believes that the problem of research done so far is completely focused on the treatment of amyloid plaques and tangles. taudue to illness causes. Schwartz's vision is completely different: the immune system.

"This is a complete paradigm change," he says. "According to our point of view, the decline in the general functioning of the immune system of Alzheimer's disease is evident. During a person's life, the system maintains the brain and maintains the balance, which, when weakened, occurs in aging, helps to develop Alzheimer's. Without taking into account the preliminary causes of the disease, the cure should pay attention to the immune system".

The immune system is presented as an army fighting against strangers that are normally infiltrated. But the system has additional roles, explained Schwartz. "Immune cells circulate in the blood and control the body and every time a balanced deviation is perceived: the invasion of a foreign element, the appearance of a predefined cell, the debris, or the tissue damage are accumulated. Over the years we thought the brain was not supervised by the immune system and the body's territory It is independent and independent In all degenerative diseases of the brain, Parkinson's disease, ALS [enfermedad de Lou Gehrig]Inflammation of the Alzheimer's brain appears; Therefore, there is a massive presence of the immune system.

"Swelling", as you can see, is a generic name for a reactive reaction of an immune system, not only due to bacterial invasion, but also tissue damage. Patients with Alzheimer's who have been receiving anti-inflammatory medications to eradicate immune cells in the brain's brain, but not only did not help them but, in many cases, worsened their condition.

"These discoveries," says Schwartz, "was consistent with our idea The brain's immune cells do not necessarily have any pathological conditions, and the presence of the brain's brain in Alzheimer's disease does not cause disease, but rather the expression of the normal attempt to cure the system".

Why this attempt did not get Alzheimer's disease: Schwartz decided to find out.

The basic idea is that it is far from the disconnection between the brain and the immune system, which is a constant and necessary connection between them.

Schwartz: "Specifically, although it has special cells in the brain, microgliaThose responsible for ongoing maintenance, in a state of anguish, are those permanent workers that are "temporary workers": cells with an immune system. They keep track of the brain and, when something is unusual (sabotage, accumulation of waste, etc.), they are damaged, they collect additional cells and take measures to restore damage. "

But how do immune cells enter the brain? After all, the blood brain barrier prevents cells and large molecules from blocking blood from the brain.

"That is correct, and the existence of that barrier is a common vision, that immune cells can not penetrate the brain, a stone-made proposal. We found a special interface, in short, to access. It is located on the roof of the brain's chamber, on the border of brain fluids and blood, and acts as a barrier to "border control." Conflicts leave the cell's immune cells in the brain or prevent them when necessary. "

So now we have Alzheimer's disease. What is wrong?

"According to our point of view, Alzheimer develops precisely Immune cells do not enter the brain and do not perform the function. Usually, waste should be eliminated, including amyloid cells and dead cells. When they do not, Amyloid builds up and begins a chain of events that cause some kind of damage. So, in reality, it's not just the right to eliminate the brain's immune cells, but the truth is the opposite: Increase the mobilization and control of the cells in order to eliminate waste".

Does the cell prevent the immune cell from penetrating the brain into Alzheimer's disease?

Msgstr "" The border crossing is blocked, one of the reasons why caregivers inhibit cells that extract the materials that open the mixes, as if it were done by hand. This inhibition is aging and even more is Alzheimer's disease. "We have found one of the proteins that are responsible for inhibiting and, when neutralized, release the cells and obtain the reverse of Alzheimer's disease".

What do you mean to "reverse Alzheimer's Disease"?

"When we released the caregivers, we allowed the immune cells to enter the brain of the Alzheimer's brain, and the cognitive abilities of the mice were rehabilitated".

The two main recommendations that are effective in preventing Alzheimer's are based on aerobic physical activity and the Mediterranean dietary diet. Credit: Bloomberg
The two main recommendations that are effective in preventing Alzheimer's are based on aerobic physical activity and the Mediterranean dietary diet. Credit: Bloomberg

Therefore, the immune system does not intervene in the brain.

"Exactly. That means that The immune system is the key to healing Alzheimer's, which is the direction we follow. In a sense, we are rejuvenating the brain. "

Sounds like anti-wrinkle promise: it softens wrinkles, stretches on the neck and rejuvenates the brain.

"Of course, we are not talking about an anti-aging product. Our research, for 20 years, constantly began to face the challenge of paradigm as a basic science. This ambition generated a great deal of opposition to us, but it also led us to develop an approach that It differs in principle from all that has been done so far in the field. Laboratory results offer good reasons for optimism. We could hardly believe the preliminary results. And, therefore, we really believe that it will be possible to "rejuvenate" the brain, in the sense of treating diseases of dementia or at least reducing deterioration".

Another reason for optimism is that Schwartz's treatment is very similar to the cancer medication that led to its developers (James P. Allison and Tasuko Honjo) to win the Nobel Prize this year. Both treatments are based on the understanding that the problem, at least in part, and the solution, are also in the functioning of the immune system. "Due to the similarity between the approaches," says Schwartz, "we hope that it is possible to reach the clinical application of our treatment with relative ease."

He talks about a paradigm shift, but also his treatment, which emerged from the new paradigm, eliminates amyloid plaques, and if so, it is not different from all that has been tried to date.

"In fact it is important to clarify this point. Our treatment mobilizes the immune system, which Not only does it eliminate amyloid plaques. It is also responsible for eliminating dead cells, healing damage and additional brain maintenance problems. We are talking about a variety of cell and a variety of materials that are excreted, and it is not even safe to know them all. That is what is so good about our approach: that even without fully understanding what is the first reason for Alzheimer's, or the second or third, It is enough if we strengthen the immune system to be successful, because we are using the natural healing system of the brain. It is not oriented to treat a particular element of Alzheimer's disease, necessarily; know how to execute the entire process ".

It's actually a "rehabilitation package".

"Exactly. At the moment the immune system is released from inhibition, we simply allow it to do its job and restore the brain to its equilibrium. Therefore, I think that a medication for Alzheimer's is a matter for the next decade. "

Less sugar, better sleep

The answer to the question of whether Alzheimer's is a genetic disease is that it is. The earlier the disease appears, the stronger the genetic component and the later it appears, the more decisive is the role of one's lifestyle. Because the disease is currently incurable, it is useful to note the possible ways to prevent it. Studies have found a number of elements that influence the development of the disease, from which recommendations are derived for behavior. In general terms, the recommendations are for the same way of life that is adequate to prevent cancer and heart disease, although mechanisms have been found that link some of the elements directly with Alzheimer's disease.

The two main recommendations that have been shown to be effective in preventing the disease or inhibiting deterioration in their early stages are aerobic physical activity (at least 30 minutes a day, three to four days a week) and nutrition based on a Mediterranean diet (fresh fruits) and vegetables, nuts and grains, olive oil, fish and dairy products, moderate quantities of chicken and red wine, and a little red meat.

In recent years, sugar has been considered as a primary risk factor, as some people call "type III diabetes" for Alzheimer's. Recently, the results of a study that supervised 5,189 people were published for a decade. He found that the higher his blood sugar levels were, the faster his cognitive impairment was. This correlation also applies to people who are not diabetic or prediabetes, but who find themselves in what is considered a normal range. In addition to this, studies suggest that the most common medication for type II diabetes, metformin (also known as Glucomin or Glucophage), protects the brain from Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases. There is evidence that even non-diabetics may benefit from taking the medication. However, because it is a generic medication and therefore it is surprisingly economical, pharmaceutical companies have no interest in investing in this research direction. Professor Slutsky demonstrated that a substance that is very similar to metformin is involved in homeostatic control in the hippocampus.

Other recommendations, whose effectiveness has not yet been definitively demonstrated but for which evidence has been found, include learning new things (auditing lectures, learning a new language and things like that) and forging social ties. Su razonamiento subyacente es la creación de “reservorios cognitivos”: las actividades cognitivas influyen en la memoria al desarrollar redes neuronales ramificadas que representan la realidad, de modo que incluso si el daño se causa en un lugar debido a las placas amiloides, la extensa red puede proponer “rutas alternativas”.

Finalmente, nunca es una exageración enfatizar la importancia de dormir lo suficiente. Los estudios han encontrado una conexión entre los ciclos de sueño y vigilia y la acumulación de placas beta amiloides en el cerebro. Los escáneres cerebrales han descubierto una acumulación de las placas en el hipocampo incluso después de una noche sin dormir. Paralelamente, surgió que las proteínas amiloides se expulsan de manera efectiva durante el sueño y no durante la vigilia. De ello se deduce que la falta de sueño puede causar o estimular el desarrollo de la enfermedad de Alzheimer, una conclusión que es consistente con la hipótesis de la profesora Schwartz sobre la participación del sistema inmunológico, que está activo principalmente por la noche, para restringir el desarrollo de la enfermedad.

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