Alzheimer's disease: a new target
The largest reduction in beta-amyloid synthesis in Alzheimer's disease has been achieved
LifeSciencesToday based on Newswise materials:
Scientists Dramatically Reduce Plaque-Forming Substances in Mice with Alzheimer’s DiseaseThe removal of one of the enzymes leads to a 90 percent reduction in the synthesis of compounds responsible for the formation of plaques associated with Alzheimer's disease in mice with a model of this disease.
This is the most significant reduction in the synthesis of beta-amyloid peptides published to date.
"These mice are a model of the most aggressive form of Alzheimer's disease. Their brains produce the largest amount of beta-amyloid peptides. This 90 percent reduction is the largest reduction in beta-amyloid levels that has been presented to date in the treatment of animal models with drugs or genetic manipulation," says the study's leader Sung Ok Yoon, PhD, associate professor of the Department of Molecular and Cellular Biochemistry at Ohio State University (Ohio State University). The study is published in the journal Neuron.
The key to reducing beta-amyloid peptides was the removal of the enzyme jnk3. This enzyme activates the amyloid precursor protein, and, consequently, its high activity enhances the synthesis of beta-amyloid peptides, increasing the likelihood of their accumulation and formation of plaques.
In addition, the researchers found that the activity of jnk3 in the brain tissues of patients with Alzheimer's disease is increased by 30-40 percent compared to normal human brain tissue. The activity of jnk3 in the brain usually remains at a low level, but increases with physiological abnormalities.
According to Professor Yun, these data suggest that jnk3 may be a new target for the treatment of Alzheimer's disease. Today, some medications can slow down the progression of this disease, but they do not cure it.
The cause of Alzheimer's disease remains unknown. But, although scientists do not yet know whether beta-amyloid peptides present in plaques are the cause of Alzheimer's disease or are formed as a consequence of the disease, the plaques themselves are associated with a progressive weakening of cognitive functions.
In this study, Dr. Yun and her colleagues genetically removed the jnk3 protein from mice carrying mutations characteristic of early-onset Alzheimer's patients. In 6 months, the synthesis of beta-amyloid peptides decreased in animals by 90 percent. This level persisted for a long period and after 12 months was 70 percent.
The removal of jnk3 also significantly improved cognitive functions – up to 80 percent of the norm, while the cognitive abilities of mice with a model of this disease were 40 percent of the norm. In addition, the removal of jnk3 in mice with Alzheimer's disease increased the number of brain neurons to 86 percent of the norm, while the number of neurons in control animals with the Alzheimer's disease model was 74 percent of the norm.
Protein jnk3 is an enzyme that modifies its target proteins and thus changes their properties. Dr. Yun and her colleagues found that jnk3 modifies the amyloid precursor protein (APP), stimulating the formation of beta-amyloid peptides.
Scientists have studied whether the removal of jnk3 leads to a change in RNA expression patterns in the brains of mice suffering from Alzheimer's disease. RNA expression patterns can tell researchers whether cells are actually behaving as expected. The result was completely unexpected: the expression of genes necessary for the synthesis of new proteins in the brains of animals with the Alzheimer's disease model was significantly reduced (compared to the brains of normal mice).
"Many neurons have stopped synthesizing proteins. And when we removed jnk3, the total volume of protein synthesis in neurons became very close to the normal level," Professor Yun comments on the results.
Experiments on neuron cultures have shown that the chain of molecular events ends with a new increase in the synthesis of beta-amyloid peptides, which suppress the synthesis of new proteins by activating another enzyme – AMP kinase (AMPK). AMPK is usually activated when cells are deficient in nutrients, for example, just before a meal. Therefore, AMPK is a popular target for the treatment of diseases associated with the use of glucose and fats by the body, such as type 2 diabetes mellitus.
Once activated, AMPK eventually suppresses a chain of chemical reactions known as the mTOR pathway that controls the synthesis of new proteins in various cell types. This phenomenon is a stress trigger of the endoplasmic reticulum (ER), a molecular machine for protein synthesis present in every cell.
Dr. Yun and her colleagues proposed a model describing their hypothesis. The constant activation of the jnk3 protein by endoplasmic reticulum stress allows a destructive cycle to begin, and over time this phenomenon intensifies as follows: an as yet unknown physiological problem increases the activity of jnk3, which leads to the initial synthesis of beta-amyloid peptides from APP. These peptides activate the AMPK enzyme. AMPK then blocks the synthesis of new proteins via the mTOR pathway. A decrease in protein synthesis leads to ER stress, and this increases the activity of jnk3. As at the beginning of the cycle, increased activity of jnk3 leads to increased synthesis of beta-amyloid peptides, giving an additional boost to the entire cycle.
To test this hypothesis, the researchers treated the living brain tissue of mice with two drugs, one of which blocks the mTOR pathway, and the other induces ER stress. In both cases, the synthesis of beta-amyloid peptides was dramatically increased within nine hours, but only in the presence of jnk3. After reviewing the data obtained in humans once again, the researchers found that pronounced ER stress is observed in the brain tissue of patients with Alzheimer's disease.
According to Professor Yun, it makes sense to test the effectiveness of various drugs that have already been developed for the treatment of other chronic progressive diseases, common to which is a violation of protein synthesis.
For example, many anti-cancer drugs are designed to block the synthesis of new proteins in cancer cells. Even though the opposite effect is desirable in Alzheimer's disease, these drugs may represent a starting point for the development of a new class of drugs for the treatment of Alzheimer's disease, Yun believes.
In addition, she is going to test whether low-molecular-weight jnk3 inhibitors can be used to improve cognitive functions in mice with Alzheimer's disease models.
The work was funded by the Alzheimer's Association and the National Institute for Neurological Disorders and Stroke.
Portal "Eternal youth" http://vechnayamolodost.ru10.09.2012