Ingrid's Lab study finds new hope for preventing memory loss in Alzheimer's disease
Have you seen "Hello, Who Am I" by Daaitai? Alzheimer's disease (AD) has become a worldwide disease with the advancement of medical treatment and the prolongation of life expectancy. According to statistics from the Ministry of Health and Welfare, the proportion of people over the age of 65 suffering from Alzheimer's disease is 5%, but when they are over the age of 85, the proportion rises to 20%! This means that the longer you live, the higher the chance of developing Alzheimer's disease. It can be said that "you can't escape that day"! 看過大愛台的「你好，我是誰」嗎？隨著醫療進步、壽命延長，阿茲海默症（Alzheimer's disease，AD）已經成為世界性的疾病。根據衛福部統計，65歲以上罹患阿茲海默症者的比例為百分之五，但到了85歲以上，這個比例上升到百分之二十！這意味著，活得愈久，罹患阿茲海默症的機率就愈高，可說是「到得這一身，難逃那一日」呢！
Alzheimer's disease accounts for about 60-70% of the elderly with dementia. There is no conclusion about the cause, but protein deposition can be observed in the brain nerve cells of patients, especially the deposition of "Aβ amyloid". Each of our brain nerve cells has as many as 10,000 synaptic connections, relying on these synaptic connections nerve cells can communicate with each other, just like a busy highway network in a metropolis.
Brain nerve cells usually rely on the so-called "autophagy" to remove unwanted or abnormally folded proteins (such as Aβ amyloid) in the cells to maintain normal cell function. When these unwanted or abnormally folded proteins increase, the inflammatory response of brain nerve cells will begin to rise, and autophagy should also rise at the same time to remove these proteins. "Autophagy" is like a kitchen waste machine, which can clean up protein waste in the brain. However, in people with aging or Alzheimer's disease, while inflammation rises in response to abnormal protein increases, autophagy does not speed up, but declines. As a result, the protein in the brain begins to accumulate, blocking the transmission of nerves, making the transmission of neural information not smooth, just like a highway traffic jam, the speed of traffic slows down, and memory defects appear. At this point, the patient begins to forget the way home, forgets his name, what he has said, and what he has done. In the end, he cannot even perform normal physiological functions.
Pavithra Suresh, a doctoral student from India to Tzu Chi University, with the encouragement of President Ingrid Liu and her team, learned the spirit of perseverance as a scientist
In the past 20 to 30 years, many research teams have tried to develop drugs to remove Aβ amyloid proteins, hoping to achieve the purpose of effectively treating Alzheimer's disease, but the results are not very effective, so many scientists have turned to reducing inflammation and other causes of cranial nerve damage. The mechanism of slow cell conduction seeks a solution. Recently, Prof. Liu Yijun, President of Tzu Chi University, found a compound of M01, which can enhance autophagy and significantly reduce the inflammatory response in brain nerve cells. Mice given M01 had improved activation of both short-term working memory and long-term gain effects (an important cellular mechanism for building long-term memory). The research results have been published in the international journal Frontiers in Aging Neuroscience with an impact factor of 5.7.
過去二三十年，許多研究團隊嘗試著開發清除Aβ類澱粉蛋白的藥物，希望能達成有效治療阿茲海默症的目的，但成效不大，所以許多科學家轉向降低發炎反應及其他造成腦神經細胞傳導變慢的機轉尋求解方。最近慈大校長劉怡均教授找到了一個M01的化合物，可以提升自噬作用，並顯著地降低腦神經細胞內的發炎反應。服用M01的小鼠，其短期工作記憶與長期增益效應（建立長期記憶的重要細胞機制）的啟動都有改善。這項研究成果已發表在影響係數5.7的國際期刊《老化神經科學前沿》（Frontiers in Aging Neuroscience）上。
WT (Wild Type, wild-type mice): normal normal experimental mice; 3xTg: mice expressing Alzheimer's symptoms. In the T-maze behavioral experiment, the movement trajectory of normal mice is significantly more than that of Alzheimer's mice; but if the Alzheimer's mice took M01, the movement trajectory was significantly restored as normal mice.
M01 is a synthetic compound. President Liu's research team found that Alzheimer's mice using M01 recovered their short-term working memory and orientation memory, which can be tested by reverse learning such as T-maze and water maze. confirmed. After taking M01, the expression of molecules related to autophagy in the hippocampus of the mouse brain increased, while the expression of inflammasome-related proteins such as NLRP3 decreased. After further testing, it was found that M01 may increase autophagy and decrease inflammatory response by regulating E3 ligase, an important molecule in the process of ubiqutination of degradable proteins. When a healthy balance is reached, the deficits in work and orientation memory caused by Alzheimer's disease can be reversed.
M01是人工合成的化合物，劉校長的研究團隊發現，使用了M01的阿茲海默小鼠，其短期工作記憶及方向記憶恢復了，這可由如T型迷宮及水迷宮的反向學習等測試證實。服用 M01後，小鼠大腦海馬迴中與自噬作用相關的分子表達增加，而發炎體相關蛋白質（如NLRP3）的表達量則減少。進一步測試後發現，M01可能是經由調節可降解蛋白質的泛蛋白化(ubiqutination)過程中的重要分子E3連接酶(E3 ligase)，使自噬作用上升、發炎反應下降，當自噬作用與發炎反應達到健康的平衡後，即可反轉阿茲海默症造成的工作及方向記憶缺損。
Interestingly, although E412, another compound studied in President Liu's laboratory, can also reverse the memory impairment caused by Alzheimer's disease, the amount of Aβ amyloid, which has always been considered to be quite critical, was tested by this compound. There were no significant changes in the brains of the treated Alzheimer's mice. This may be because the mice used in the experiment have just developed the disease and have not accumulated a lot of Aβ amyloid, or it may be that the efficacy of E412 is not related to the change in the amount of Aβ amyloid. Comparing with the recent news about Aβ*56 amyloid, the findings of President Liu's research team also remind us that the cause of Alzheimer's disease is actually quite complicated. Is Aβ amyloid the cause of Alzheimer's disease? Or fruit? Scientists are still exploring. Aβ*56 is only one type of amyloid. In the past few decades, the main research has focused on Aβ40 and Aβ42. Therefore, the Aβ*56 paper storm will not cause the amyloid hypothesis. Ineffective, but based on Aβ*56-like amyloid research, the interpretation of the experimental results must be re-examined. In the past, studies have also found that nuns who keep writing diaries, although there is still accumulation of Aβ-like amyloid in the brain nerve cells after death, their cognitive function does not decline. Therefore, to what extent amyloid accumulation can be handled, and to what extent cannot be recovered should be the focus of scientists now. It is like a forest fire that starts from a spark. When a spark is found, that is, when the level of amyloid accumulation still does not affect memory function, it may be too late to put it out in time. If a forest fire is caused, then use more firefighters. , no amount of water and compounds may be too late.
HECT-E3 ligase is a member of the "E3 ligase" family, and their function is to attach unwanted or abnormally folded proteins to ubiquitin. After ubiquitin is attached to the protein, it will be broken down by the process of ubiquitination. There are 500 to 1,000 known E3 ligases, and they are like environmental bodhisattvas in cells, responsible for tagging unwanted things to break down. HECT-E3 ligase is responsible for processing proteins that initiate autophagy, such as Beclin-1. When the autophagy function is low, if the HECT-E3 ligase can be regulated, its working efficiency will be slightly reduced to improve autophagy. It can maintain the elimination of abnormal protein in the brain.
The research team of President Liu Yijun will continue to study the mechanism of action of M01. Through the cooperation with Professor Xu Haoren, the head of the Department of Biological Sciences, we will use molecular simulation to find out whether there are other E3 ligases other than HECT-E3 ligase. M01 interacts to select potential drug candidate molecules. In addition, President Liu's research team has also invested in the research and development of other herbal compounds that can reverse the memory degradation of Alzheimer's disease, hoping to effectively prevent and treat memory degradation caused by Alzheimer's disease in the near future.
Pavithra Suresh et. al., 2022. Attenuation of HECT-E3 ligase expression rescued memory deficits in 3xTg-AD mice. Frontiers in Aging Neuroscience. doi: 10.3389/fnagi.2022.916904