North American discovery points out key to understanding Alzheimer's
In the last 15 years, the understanding of Alzheimer's disease has taken a leap, with the identification of proteins that, modified, progressively destroy neurons , causing well-established symptoms of cognitive and functional loss in patients. However, this knowledge did not translate into clinical benefits, and all potential drugs failed the tests. Now, researchers at the University of Alabama, Birmingham (USA), claim to have found the missing piece to close the puzzle of this disease, which is expected to reach 152 million cases by 2050, according to the World Health Organization ( WHO).
In an article published in the journal Science Translational Medicine, the team of researchers demonstrates the importance of a third character in the pathology: the neurotransmitter norepinephrine, also known as norepinephrine. Tests with mice and human brain tissues revealed that blocking a receptor for this natural substance produced by the brain favors the toxic effect that characterizes the deterioration of the beta-amyloid protein. In addition, scientists found that drugs already on the market were able, in mice, to slow the progression of neurodegeneration and restore cognitive functions.
"Our study provides new insights into the mechanisms underlying beta-amyloid protein toxicity that may have strong implications for future drug design," says Qin Wang, professor of cell biology, development and integrative biology and research leader. "It identifies an attractive and specific therapeutic target for Alzheimer's disease." According to her, the pathological mechanism identified in the study may also explain why several clinical trials aimed at reducing the accumulation of amyloid protein in the brain have failed.
The biologist says that it is already known that the excess of fatty pieces of beta-amyloid in the brain acts as a trigger to induce changes in another protein, tau. Modified, it becomes a destroyer of neurons, which characterizes Alzheimer's disease. However, the path between these two mechanisms was unknown until now. In brain tissue tests of patients who died from the disease, scientists found that beta-amyloid plaques hijack norepinephrine signaling in neurons. These, in turn, redirect this signal to activate an enzyme called GSK3-beta. Activated, it makes tau toxic to brain cells.
This occurs at a cell membrane receptor on the surface of neurons called alpha-2A. Membrane receptors are specific proteins for certain molecules: when they come into contact with them, they trigger chemical reactions within the cell. In this case, neurons. Wang explains that although the accumulation of beta-amyloid plaques activates the enzyme GSK3-beta, the presence of norepinephrine doubled the signaling for it to take action and thus promote the toxicity of tau proteins.
The researchers found that, in the cortex tissue of patients who died from the disease, the alpha-2A adrenergic receptor was significantly increased, which supports their hypothesis. Another piece of information that supports the existence of this mechanism is an epidemiological study by the National Center for Coordination of Alzheimer, in the United States. He showed that the use of the drug clonidine - an alpha-2A activator - used to lower blood pressure, worsened cognitive function in patients who already had this type of deficit. In addition, the adverse effects of the substance were stronger in patients with severe dementia. The use of clonidine did not cause changes in individuals with normal cognition.
"Our study provides new insights into the mechanisms underlying beta-amyloid protein toxicity that may have strong implications for future drug design," says Qin Wang, professor of cell biology, development and integrative biology and research leader. "It identifies an attractive and specific therapeutic target for Alzheimer's disease." According to her, the pathological mechanism identified in the study may also explain why several clinical trials aimed at reducing the accumulation of amyloid protein in the brain have failed.
The biologist says that it is already known that the excess of fatty pieces of beta-amyloid in the brain acts as a trigger to induce changes in another protein, tau. Modified, it becomes a destroyer of neurons, which characterizes Alzheimer's disease. However, the path between these two mechanisms was unknown until now. In brain tissue tests of patients who died from the disease, scientists found that beta-amyloid plaques hijack norepinephrine signaling in neurons. These, in turn, redirect this signal to activate an enzyme called GSK3-beta. Activated, it makes tau toxic to brain cells.
This occurs at a cell membrane receptor on the surface of neurons called alpha-2A. Membrane receptors are specific proteins for certain molecules: when they come into contact with them, they trigger chemical reactions within the cell. In this case, neurons. Wang explains that although the accumulation of beta-amyloid plaques activates the enzyme GSK3-beta, the presence of norepinephrine doubled the signaling for it to take action and thus promote the toxicity of tau proteins.
The researchers found that, in the cortex tissue of patients who died from the disease, the alpha-2A adrenergic receptor was significantly increased, which supports their hypothesis. Another piece of information that supports the existence of this mechanism is an epidemiological study by the National Center for Coordination of Alzheimer, in the United States. He showed that the use of the drug clonidine - an alpha-2A activator - used to lower blood pressure, worsened cognitive function in patients who already had this type of deficit. In addition, the adverse effects of the substance were stronger in patients with severe dementia. The use of clonidine did not cause changes in individuals with normal cognition.
Promising tests
In another part of the study, the team tested an existing drug - idazoxan - on a mouse model of Alzheimer's disease. This substance is an alpha-2A antagonist that is being researched in clinical trials for depression. The hypothesis was that, by blocking the action of the receptor in animals with a pathology similar to Alzheimer's, the drug could act directly against the disease.
The mice were treated for eight weeks from the age of 8 months, a time when beta-amyloid plaques are already present in the brain and the alpha-2A adrenergic receptor is at work. Compared to the control group, the animals that received the substance showed several improvements. Idazoxan reversed the hyperactivation of the GSK3-beta enzyme; there was a reduction in the accumulation of beta-amyloid plaques in the cerebral cortex; the tau protein has undergone fewer changes and, consequently, has become less toxic; and performance on cognitive tests was almost as good as that of normal mice and significantly better compared to untreated Alzheimer's model mice.
"Alpha-2A adrenergic receptor blockers, such as idazoxan, were developed for use in other disorders, and the reuse of these drugs can be a potentially effective and readily available strategy for the treatment of Alzheimer's disease," says Wang. "In addition, our data suggest that alpha-2A is an attractive and specific therapeutic target for Alzheimer's disease," he notes.
The mice were treated for eight weeks from the age of 8 months, a time when beta-amyloid plaques are already present in the brain and the alpha-2A adrenergic receptor is at work. Compared to the control group, the animals that received the substance showed several improvements. Idazoxan reversed the hyperactivation of the GSK3-beta enzyme; there was a reduction in the accumulation of beta-amyloid plaques in the cerebral cortex; the tau protein has undergone fewer changes and, consequently, has become less toxic; and performance on cognitive tests was almost as good as that of normal mice and significantly better compared to untreated Alzheimer's model mice.
"Alpha-2A adrenergic receptor blockers, such as idazoxan, were developed for use in other disorders, and the reuse of these drugs can be a potentially effective and readily available strategy for the treatment of Alzheimer's disease," says Wang. "In addition, our data suggest that alpha-2A is an attractive and specific therapeutic target for Alzheimer's disease," he notes.
Expert word
Another brick
“We know that the gear by which the disease destroys the brain has two fronts: one is the beta-amyloid protein and the other is the tau protein. But today, what the majority of the scientific community understands is that this theory must be contained in something greater. And then we need to know that other mechanisms would activate this amyloid cascade. Within this scenario, researchers at the University of Alabama publish the study showing that norepinephrine may play a role in this, and not only speculate, but do a very elegant, three-phase experimental study. Studying brain tissue, the researchers saw that there was a certain receptor, which is that of norepinephrine, which, when blocked, causes an increase in an enzyme, GSK3 - this one, well known for its involvement in this amyloid cascade. The main result of the study is to show the metabolic path of this gear, it is to put another brick on the wall of scientific knowledge in this area. This opens up the potential for new treatment development fronts to be made. But we are talking about animal model. Until you get to a molecule and test it on humans, it would be at least eight years. The other interesting side is that we have other drugs that act on norepinephrine. Even some antidepressants used routinely on the market. Some of them could, indeed, have a beneficial effect on the disease. So, it opens a door for existing drugs to be tested for their possible collaboration in the treatment of Alzheimer's disease. "Otávio Castelo, president of the Brazilian Alzheimer's Association, regional DF (Abraz / DF). is to put another brick on the wall of scientific knowledge in this area. This opens up the potential for new treatment development fronts to be made. But we are talking about animal model. Until you get to a molecule and test it on humans, it would be at least eight years. The other interesting side is that we have other drugs that act on norepinephrine. Even some antidepressants used routinely on the market. Some of them could, indeed, have a beneficial effect on the disease. So, it opens a door for existing drugs to be tested for their possible collaboration in the treatment of Alzheimer's disease. "Otávio Castelo, president of the Brazilian Alzheimer's Association, regional DF (Abraz / DF). is to put another brick on the wall of scientific knowledge in this area. This opens up the potential for new treatment development fronts to be made. But we are talking about animal model. Until you get to a molecule and test it on humans, it would be at least eight years. The other interesting side is that we have other drugs that act on norepinephrine. Even some antidepressants used routinely on the market. Some of them could, indeed, have a beneficial effect on the disease. So, it opens a door for existing drugs to be tested for their possible collaboration in the treatment of Alzheimer's disease. "Otávio Castelo, president of the Brazilian Alzheimer's Association, regional DF (Abraz / DF). This opens up the potential for new treatment development fronts to be made. But we are talking about animal model. Until you get to a molecule and test it on humans, it would be at least eight years. The other interesting side is that we have other drugs that act on norepinephrine. Even some antidepressants used routinely on the market. Some of them could, indeed, have a beneficial effect on the disease. So, it opens a door for existing drugs to be tested for their possible collaboration in the treatment of Alzheimer's disease. "Otávio Castelo, president of the Brazilian Alzheimer's Association, regional DF (Abraz / DF). This opens up the potential for new treatment development fronts to be made. But we are talking about animal model. Until you reach a molecule and test it on humans, it would be at least eight years. The other interesting side is that we have other drugs that act on norepinephrine. Even some antidepressants used routinely on the market. Some of them could, indeed, have a beneficial effect on the disease. So, it opens a door for existing drugs to be tested for their possible collaboration in the treatment of Alzheimer's disease. "Otávio Castelo, president of the Brazilian Alzheimer's Association, regional DF (Abraz / DF). The other interesting side is that we have other drugs that act on norepinephrine. Even some antidepressants used routinely on the market. Some of them could, indeed, have a beneficial effect on the disease. So, it opens a door for existing drugs to be tested for their possible collaboration in the treatment of Alzheimer's disease. "Otávio Castelo, president of the Brazilian Alzheimer's Association, regional DF (Abraz / DF). The other interesting side is that we have other drugs that act on norepinephrine. Even some antidepressants used routinely on the market. Some of them could, indeed, have a beneficial effect on the disease. So, it opens a door for existing drugs to be tested for their possible collaboration in the treatment of Alzheimer's disease.
“We know that the gear by which the disease destroys the brain has two fronts: one is the beta-amyloid protein and the other is the tau protein. But today, what the majority of the scientific community understands is that this theory must be contained in something greater. And then we need to know that other mechanisms would activate this amyloid cascade. Within this scenario, researchers at the University of Alabama publish the study showing that norepinephrine may play a role in this, and not only speculate, but do a very elegant, three-phase experimental study. Studying brain tissue, the researchers saw that there was a certain receptor, which is that of norepinephrine, which, when blocked, causes an increase in an enzyme, GSK3 - this one, well known for its involvement in this amyloid cascade. The main result of the study is to show the metabolic path of this gear, it is to put another brick on the wall of scientific knowledge in this area. This opens up the potential for new treatment development fronts to be made. But we are talking about animal model. Until you get to a molecule and test it on humans, it would be at least eight years. The other interesting side is that we have other drugs that act on norepinephrine. Even some antidepressants used routinely on the market. Some of them could, indeed, have a beneficial effect on the disease. So, it opens a door for existing drugs to be tested for their possible collaboration in the treatment of Alzheimer's disease. "Otávio Castelo, president of the Brazilian Alzheimer's Association, regional DF (Abraz / DF). is to put another brick on the wall of scientific knowledge in this area. This opens up the potential for new treatment development fronts to be made. But we are talking about animal model. Until you get to a molecule and test it on humans, it would be at least eight years. The other interesting side is that we have other drugs that act on norepinephrine. Even some antidepressants used routinely on the market. Some of them could, indeed, have a beneficial effect on the disease. So, it opens a door for existing drugs to be tested for their possible collaboration in the treatment of Alzheimer's disease. "Otávio Castelo, president of the Brazilian Alzheimer's Association, regional DF (Abraz / DF). is to put another brick on the wall of scientific knowledge in this area. This opens up the potential for new treatment development fronts to be made. But we are talking about animal model. Until you get to a molecule and test it on humans, it would be at least eight years. The other interesting side is that we have other drugs that act on norepinephrine. Even some antidepressants used routinely on the market. Some of them could, indeed, have a beneficial effect on the disease. So, it opens a door for existing drugs to be tested for their possible collaboration in the treatment of Alzheimer's disease. "Otávio Castelo, president of the Brazilian Alzheimer's Association, regional DF (Abraz / DF). This opens up the potential for new treatment development fronts to be made. But we are talking about animal model. Until you get to a molecule and test it on humans, it would be at least eight years. The other interesting side is that we have other drugs that act on norepinephrine. Even some antidepressants used routinely on the market. Some of them could, indeed, have a beneficial effect on the disease. So, it opens a door for existing drugs to be tested for their possible collaboration in the treatment of Alzheimer's disease. "Otávio Castelo, president of the Brazilian Alzheimer's Association, regional DF (Abraz / DF). This opens up the potential for new treatment development fronts to be made. But we are talking about animal model. Until you reach a molecule and test it on humans, it would be at least eight years. The other interesting side is that we have other drugs that act on norepinephrine. Even some antidepressants used routinely on the market. Some of them could, indeed, have a beneficial effect on the disease. So, it opens a door for existing drugs to be tested for their possible collaboration in the treatment of Alzheimer's disease. "Otávio Castelo, president of the Brazilian Alzheimer's Association, regional DF (Abraz / DF). The other interesting side is that we have other drugs that act on norepinephrine. Even some antidepressants used routinely on the market. Some of them could, indeed, have a beneficial effect on the disease. So, it opens a door for existing drugs to be tested for their possible collaboration in the treatment of Alzheimer's disease. "Otávio Castelo, president of the Brazilian Alzheimer's Association, regional DF (Abraz / DF). The other interesting side is that we have other drugs that act on norepinephrine. Even some antidepressants used routinely on the market. Some of them could, indeed, have a beneficial effect on the disease. So, it opens a door for existing drugs to be tested for their possible collaboration in the treatment of Alzheimer's disease.
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