The abnormal brain activity is caused by a failure in the regulatory mechanism and may be used for early diagnosis already in the dormant stage of the disease
"Despite many efforts throughout the world over many years, there is still no effective cure for Alzheimer's disease," says Prof. Ina Slutsky from the medical school. "With the increase in life expectancy, the disease becomes a major health and economic problem in the Western world. According to a study recently published in the journal Lancet Public Health Journal The number of dementia sufferers worldwide is expected to increase from 50 million in 2019 to more than 150 million in 2050. In North Africa and the Middle East an increase of approximately 370% is expected, in Israel approximately 145%, and in Western Europe approximately 74%. The surge in the spread of Alzheimer's disease is expected to continue, as a result of the expected increase in the population and life expectancy - if we cannot develop effective treatments. This is a warning light that calls for expanded and accelerated investment in dementia research, with an emphasis on its most common form - Alzheimer's disease."
"Innovative imaging technologies developed in recent years have revealed that amyloid deposits that characterize Alzheimer's disease form in the brains of patients as early as 20-10 years before the appearance of the familiar symptoms of memory impairment and cognitive decline. Unfortunately, to date, most efforts to treat Alzheimer's by lowering the amount of the protein that makes up the deposits (amyloid-beta) have failed. However, if we could diagnose the disease at an early stage and then leave it in a 'dormant' and pre-symptomatic state for many years, this would be a tremendous achievement that might save the quality of life of millions of patients. We believe that identifying and deciphering a characteristic signature of electrical brain activity in the pre-symptomatic stages of Alzheimer's is a key to effective treatment."
The researchers, from the School of Medicine andfrom the Segol School of Brain Research At Tel Aviv University, led by Prof. Ina Slutsky and doctoral students Daniel Zarhin and Raphaela Atzmon, they uncovered a pathological brain phenomenon that precedes the first appearance of Alzheimer's disease symptoms by many years. This is an increased activity in the hippocampus in the states of anesthesia and sleep, which results from damage to the mechanism that stabilizes the neural network. According to them, the unusual phenomenon may allow an early diagnosis of Alzheimer's disease, which may lead to more effective treatment of the disease, which is considered incurable to this day.
Participants in the study: Dr. Antonella Ruggiero, Halit Ballouh, Shiri Shub, Oded Sharaf, Lior Haim, Nadav Buchbinder, Ortel Shinikamain, Dr. Ilana Shapira, Dr. Boaz Steer, and Dr. Gabriela Brown from Prof. Slutsky's laboratory, In collaboration with the laboratory of Prof. Yaniv Ziv from the Weizmann Institute, and the laboratories of Prof. Yuval Nir, Prof. Tamar Geiger, and Dr. Anton Sheinin from Tel Aviv University, and researchers from Japan. The article was published in the journal Cell reports.
The researchers used Alzheimer's model mice and focused on the hippocampus region of the brain, which plays a central role in memory processes, and is known to be damaged in Alzheimer's patients. First, they measured the activity of cells in the hippocampus while the mouse is awake, active, and exploring its environment - using advanced methods that measure brain activity at the resolution of individual nerve cells (neurons). According to Daniel Zarhin, "Previous studies examined the activity of the cells in the brains of anesthetized model mice, and found hyperactivity in the hippocampus and cerebral cortex. To my surprise, when I tested awake and active mice, I found no difference between the activity of neurons and synapses in the brains of sick mice compared to a control group of healthy mice."
High neural activity also during sleep
In light of the findings, the researchers wanted to examine the activity in the hippocampus in different states of consciousness - during anesthesia or natural sleep. According to Raphaela Atzmon, "It is known that in healthy animals the neural activity in the hippocampus decreases during sleep. But when I tested early-stage Alzheimer's disease model mice, I discovered that the neural activity in the hippocampus remains high even during sleep. This is a failed regulation of the activity of cells in the hippocampus that has not been observed to date in the context of Alzheimer's disease." Daniel Zarhin found similar disturbances in the model mice under anesthesia: the activity of the neurons does not weaken, the neurons work in an overly synchronized manner, and a pathological electrical pattern is created similar to 'silent' seizures in epilepsy patients. Helit Baloah, who studies sleep problems related to Alzheimer's disease, emphasizes that the disorder that was discovered begins before the sleep disorders characteristic of Alzheimer's patients appear.
Prof. Slutsky: "In fact, we discovered that brain states that block response to the environment - such as sleep and anesthesia - reveal the abnormal activity that remains hidden in waking states, and this happens even before the familiar symptoms of Alzheimer's disease are observed. Although the same abnormal activity is also detectable during sleep, its frequency is much higher under anesthesia. That's why it's important to check if short anesthesia can be used for early diagnosis of the disease."
In the next step, the researchers wanted to find out what causes the unusual phenomenon. For this purpose, they relied on conclusions from previous studies by Prof. Slutsky's laboratory and other researchers on the homeostasis (state of balance) of neural networks: in each neural circuit there is a balance point, and next to it is a stabilizing mechanism that comes into action when the balance is disturbed, and its role is to return the neural activity to the original balance point. Is damage to this mechanism the main cause of negative dysregulation of brain activity during sleep or anesthesia in Alzheimer's model mice? To test this, Dr. Antonella Ruggiero grew neuronal networks from the hippocampus of sick and healthy mice, and performed a series of experiments on them in the laboratory. First she examined the effect of different anesthetic drugs on the neurons and found that they lower the balance point of the neural activity. In neuronal networks taken from healthy mice, the activity remains low over time, but in the neuronal networks of the Alzheimer's model mice, the activity fails to maintain the low balance point and immediately rises back up, despite the presence of the anesthetics. In another experiment, Dr. Ruggiero increased the activity of the nerve cells, and here, too, she found that in the group of model mice there is a failure in the mechanism that is supposed to return the activity to the normal balance point.
The drug that reduces and stabilizes brain activity
Now the researchers wanted to test a potential drug for the damaged regulatory mechanism. Prof. Slutsky: "The phenomenon of instability in neural activity that we found in this study is known from epilepsy. In a previous study, we discovered that an existing drug for multiple sclerosis may help epilepsy patients by activating a homeostatic mechanism that lowers the balance point of neural activity. Doctoral student Shiri again tested the effect of the drug on the activity of the hippocampus in Alzheimer's model mice, and found that in this case too the drug stabilizes the activity and reduces the pathological activity observed during anesthesia."
Prof. Slutsky summarizes: "Our research brought up a number of findings with the potential for early diagnosis of Alzheimer's, and even for providing a response to the disease. First, we found that states of anesthesia and sleep reveal pathological brain activity in the early stages of Alzheimer's disease, before the onset of cognitive problems. Second, we discovered the cause of the pathological activity - damage to a basic mechanism that stabilizes the electrical activity in brain circuits. And thirdly, we offer a well-known drug for multiple sclerosis that, after adjustment, may also help Alzheimer's patients following early detection."
The researchers now plan to collaborate with medical centers in Israel and around the world in order to examine whether the mechanisms revealed in the model mice can also be identified in Alzheimer's patients in the early stages of the disease. For this purpose, they request to integrate A.A.G. monitoring. In surgical procedures, in order to measure the brain activity of the operated on during anesthesia. They hope that the findings will advance the development of drugs that will help patients following early detection of Alzheimer's disease.
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