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.

在老年失智的族群中,阿茲海默症佔了大約六到七成。關於病因,目前還沒有定論,但是在患者的腦神經細胞中可以觀察到蛋白質沈積的現象,尤其以「Aβ類澱粉蛋白」的沈積最為明顯。我們的每一條腦神經細胞都有多達一萬個突觸連結點,靠著這些突觸連結點神經細胞可以互通消息,就像大都市中繁忙的公路網一般。


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.

腦神經細胞平常靠著稱為「自噬作用」(autophagy)來清除細胞中不需要、或不正常折疊的蛋白質(如Aβ類澱粉蛋白),來讓細胞維持正常的功能。當這些不需要或不正常折疊的蛋白質增加的時候,腦神經細胞的發炎反應會開始上升,這時候自噬作用也應該要同時上升,才能將這些蛋白質們清除乾淨。「自噬作用」就像廚餘機,可以清理腦中的蛋白質廢棄物。然而,在老化或阿茲海默症的人,雖然發炎反應會因應不正常的蛋白質增加而上升,自噬作用卻沒有隨之加速,反而下降了。如此一來,腦中的蛋白質就開始囤積,塞住神經的傳導,使得神經信息的傳遞不順暢,就像高速公路塞車般,車流速度慢了下來,記憶就出現了缺損。此時,患者開始記不得回家的路、忘記自己的名字、說過的話、作過的事,到最後連正常的生理功能都無法執行。

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.

有意思的是,在劉校長實驗室中研究的另一項化合物E412雖然也可以反轉阿茲海默症造成的記憶缺損,但一向被認為相當關鍵的Aβ類澱粉蛋白的量,在經此化合物處理過的阿茲海默小鼠腦中並沒有明顯變化。這可能是因為實驗中使用的小鼠們剛發病,累積的Aβ類澱粉蛋白還不多,也可能是E412的功效與Aβ類澱粉蛋白量的變化不相關。對照最近關於Aβ*56類澱粉蛋白的新聞,劉校長研究團隊的發現也提醒了我們,關於阿茲海默症的成因其實相當複雜,究竟Aβ類澱粉蛋白是阿茲海默症的因?亦或是果?科學家們仍在探索,Aβ*56只是類澱粉蛋白中的一個類型,過去幾十年來主要的研究都集中在Aβ40及Aβ42,因此此次Aβ*56的論文風波並不會造成類澱粉蛋白假說的失效,而是奠基於Aβ*56類澱粉蛋白的研究必須重新檢視實驗結果的闡釋。過去也曾有研究發現,持續寫日記的修女,雖然往生後腦神經細胞中仍有Aβ類澱粉蛋白堆積,但她們的認知功能並未衰退。因此,類澱粉蛋白的堆積到什麼程度是可以處理的,到了什麼嚴重的程度就無法挽回應該是科學家們現在要聚焦的重點。好比森林大火起於星星之火,當發現星火時,也就是類澱粉蛋白堆積的程度仍不至於影響記憶功能時,及時撲滅或許還來得及,如果一旦釀成森林大火,那麼動用再多的消防隊員,再多的水和化合物可能都為時已晚。

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.

HECT-E3連接酶是「E3連接酶」家族的成員之一,它們的功能就是將不需要或不正常折疊的蛋白質接上泛素(ubiquitin)。接上泛素以後的蛋白質,就會被泛蛋白化的過程分解掉。目前已知的E3連接酶有五百到一千個,它們就像細胞中的環保菩薩,負責把不需要的東西加上標籤以進行分解。HECT-E3連接酶負責處理啟動自噬作用的蛋白像是Beclin-1,當自噬作用功能低下時,若能調節HECT-E3連接酶,使它的工作效率稍降,以提升自噬作用,就可維持大腦內對於不正常蛋白質的清消。


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.

劉怡均校長的研究團隊將會繼續研究M01的作用機轉,透過與生科系主任許豪仁教授的合作,以分子模擬的方式找出除了HECT-E3連接酶以外,是否有其他的E3連接酶與M01有互動,選擇出有潛力的藥物候選分子。另外,劉校長的研究團隊也投入研發其他能反轉阿茲海默症記憶退化的草藥化合物,希望在不久的將來,能有效地預防、治療阿茲海默症引發的記憶退化。

References:

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

撰文/葉綠舒;攝影/曾繼鋒

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