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The balance point - on the way to understanding Alzheimer's disease

Disruption of the activity rate of neural networks is related to the development of Alzheimer's disease

The Alzheimer's conundrum. Illustration:
The Alzheimer's conundrum. Illustration:

Alzheimer's disease has been studied for over 100 years, and there are still question marks regarding its causes and the possibilities of preventing or curing it. In the last 30 years, much progress has been made in understanding the biochemistry of the disease, and in particular in understanding the role of the amyloid beta protein, which plays a central role in it. This protein is also present in the healthy, and not only in the sick; But in Alzheimer's disease (and also in other diseases - Parkinson's disease for example), its properties change and it organizes into clusters that form characteristic deposits in the brain. Many researchers have tried to find a drug that will reduce the production of this protein or prevent its accumulation in sediments. But so far, drugs of this type have not improved the condition of the patients.What is the question? What is the cause of memory impairment, typical of Alzheimer's disease?

Prof. Ina Slutsky, from the Faculty of Medicine at Tel Aviv University, believes that it is impossible to understand the disease without understanding the role of the protein in the healthy brain. Her research, which won a research grant from the National Science Foundation, aims to identify the role of this protein.

A very small percentage of all Alzheimer's patients - less than two percent - have a genetic mutation that causes a change in the amount or properties of the amyloid beta protein. But the rest of the patients, who are the vast majority, do not have such a mutation, and we do not know what caused their disease: other mutations that have a weaker effect, or environmental factors. Apparently, we have a dead end ahead of us. But in order to develop a cure, is it really important that we know the cause of the disease - or is it enough to understand the course of its development?

Already at an early stage during Alzheimer's disease, before the symptoms appear, there are disruptions in the basic system that maintains stable activity in the relevant nerve networks. A state of stability and constant conditions in a certain environment is called homeostasis, and a system that maintains such stability is called a homeostatic system. One of the examples of maintaining homeostasis is the fairly constant temperature of the human body (and of the bodies of mammals and birds in general). Prof. Slutsky and her colleagues believe that a failure of the homeostatic system is the cause of the deterioration in neural activity, and as a result - the dismal deterioration in mental (cognitive) function that characterizes the disease. There are sensors in the brain that are sensitive to a variety of changes, including changes in the frequency of activity of the neural networks. When these sensors are activated they cause a negative feedback, reducing the change that activated them

When their condition is normal and stable, the nerve networks in the brain operate at a certain frequency. This constant frequency is the "balance point" (set point) of the neural networks. Prof. Slutsky showed that the mitochondria - the "powerhouses of the cell" - play an important role in determining this balance point. In the brain there are sensors that are sensitive to a variety of changes, including changes in the frequency of activity of the neural networks. When these sensors are activated they cause a negative feedback, reducing the change that activated them. In this way, the system returns to normal operation. However, it is not clear how this process occurs in neural networks: what are those sensors and how they create a negative feedback that maintains the balance point.

Using a combination of measurement technologies and computational tools, Prof. Slutsky identified an active protein (enzyme) involved in determining the balance point of neural networks. This enzyme is called DHODH, and as she guessed, it is indeed found and works in the mitochondria. Inhibition of this enzyme causes a decrease in the frequency of activity of nerve networks - that is, their balance point can be changed and is not genetically fixed.

This finding links to an important medical finding about Alzheimer's patients: during sleep, abnormal epilepsy-like activity occurs in their brains. In general, the balance point of the activity frequency of the neural networks decreases during sleep and increases during wakefulness; Prof. Slutsky therefore hypothesized that the disturbances in the rhythm of activity in the brains of Alzheimer's patients result from a change in the balance point during sleep. Sleep is of enormous importance in the normal functioning of the brain; Disruptions in brain activity during sleep in Alzheimer's patients may therefore explain the impairment of memory characteristic of this disease.

To identify the disruption in the system, Prof. Slutsky and her group created several innovative research systems. One of them makes it possible to measure the activity of thousands of nerve cells in the hippocampus of mice, with a resolution that distinguishes the activity of single cells; The hippocampus is an area deep in the brain, and such a precise measurement in this area is therefore a new achievement. The researchers measure the activity in the brains of mice used as a model for Alzheimer's disease, and check the changes in activity even before the symptoms and memory impairment appear. Prof. Slutsky hypothesized that the disruptions in the rate of activity in the brains of Alzheimer's patients result from a change in the balance point during sleep.

Along with this method, which is at the level of the complete and living animal, the research group also uses simple neural networks grown in an incubator, as well as advanced imaging methods. "Most research groups in the world use a model of animals behaving freely, or neural networks growing in an incubator," says Prof. Slutsky. "We combine the two models, and hope that the combination will help us identify the disruption in the balance point at the molecular level. After we identify this disruption, we will try to come up with a treatment that will stop the progression of the disease and the damage to memory."

Prof. Ina Slutsky

Life itself:

Prof. Ina Slutsky used to play the piano in the past; Today she prefers to listen

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