Tzu Chi University Research Team Finds Hope for Preventing Memory Loss Caused by Alzheimer’s Disease

Have you watched the Da Ai TV program “Hello, Who Am I?” Alzheimer’s disease (AD) has become a worldwide disease, along with the advancement of healthcare and the prolongation of life expectancy. Based on statistics provided by the Ministry of Health and Welfare, around 5% of Taiwanese people over 65 have Alzheimer’s disease, and 20% of those over 85 have it. These statistics reveal that the longer we live, the higher our chance of developing Alzheimer’s.

Alzheimer’s disease accounts for 60 to 70% of elderly persons with dementia. There is no conclusion about the cause, but protein deposition can be observed in the brain cells of patients, especially the deposit of “Aβ amyloid.” Each of our brain nerve cells has as many as 10,000 synaptic connections. Through these synaptic connections, nerve cells can communicate with each other like a metropolis’ busy freeway network.

Brain nerve cells usually rely on autophagy to remove unwanted or abnormal protein folding (such as Aβ amyloid) in cells to maintain normal cell function. When undesirable or abnormal protein folding increases, the inflammatory responses of brain nerve cells will begin to rise and autophagy will also increase, at the same time, to remove these proteins. “Autophagy” is like a kitchen garbage disposal unit, and it can clean up protein waste in the brain.

However, in people with aging or Alzheimer’s disease, while their inflammation rises in response to abnormal protein increase, autophagy does not speed up, but declines, instead. As a result, abnormal proteins in their brains begin to accumulate, blocking nerves transmission, making transmission of nerve information irregular; just like in a traffic jam, traffic speed slows down, and the memory becomes defective. At this point, they will forget the way home, will not remember their names, forget what they just said or what they have done. In the end, they cannot even perform normal physiological functions.

For the past 20 to 30 years, many research teams have tried to develop drugs to remove Aβ amyloid, hoping to treat Alzheimer’s disease, but the results have not been satisfactory. Many scientists turned to lowering inflammation or worked on other mechanisms that slow nerve cell conduction in the brain.

Recently, University President Ingrid Liu’s research team found a compound of M01, which can enhance autophagy and significantly reduce the inflammatory response in brain nerve cells. Mice given M01 displayed improved activation of both short-term working memory and long-term potentiation (an essential cellular mechanism for building long-term memory). The team has published its research findings in an international journal, “Frontiers in Aging Neuroscience,” with an impact factor of 5.7.

M01 is a synthetic compound. President Liu’s team found that Alzheimer’s mice using M01 recovered their short-term working memory and orientation memory, which could be tested by reverse learning, such as a T-maze or water maze. After taking M01, the expression of molecules related to autophagy in the hippocampus of the mouse brains increased, while the expression of inflammasome-related proteins, such as NLRP3 decreased.

After further testing, the team found that M01 may increase autophagy and decrease inflammatory response by regulating E3 ligase, an essential molecule in the ubiquitination of degradable proteins. When a healthy balance is reached, it can reverse the deficits caused by Alzheimer’s disease in working and orientation memory.

Interestingly, although E412, another compound studied in President Liu’s laboratory, can also reverse memory impairment caused by Alzheimer’s disease, the amount of Aβ amyloid, which has always been quite critical, was tested by this compound. However, there were no significant changes in the treated Alzheimer’s mice’s brains.

This may be due to the fact that mice involved in the experiment had just developed the disease and had not accumulated much Aβ amyloid, or it may be that the efficacy of E412 is not related to change in the amount of Aβ amyloid. In contrast to recent news about Aβ*56 amyloid, the findings of President Liu’s team also remind us that the causes of Alzheimer’s disease are quite complex. Is Aβ amyloid the cause of Alzheimer’s disease? Or the result?

Scientists are still exploring. Aβ*56 is only one type of amyloid. In the past few decades, researchers have focused their endeavors on Aβ40 and Aβ42. Therefore, research issues related to Aβ*56 will not cause the researcher to deny the amyloid hypothesis. Instead, researchers will continue to work on Aβ*56 amyloid research to reexamine previous research findings.

Studies have also found that a Catholic nun who kept writing diaries in her lifetime had accumulations of Aβ amyloid in the brain nerve cells after death, and her cognitive functions did not decline. Therefore, scientists should focus on studying to what extent people with amyloid accumulation can normally live their daily lives, and under what circumstances they cannot.

A forest fire starts from a spark. Similarly, when the level of amyloid accumulation still does not affect memory function, we can do something to put it out in time. If the spark has spread to become a severe forest fire, no matter how many firefighters participate, or how much water and compounds they use, it will be too late.

HECT-E3 ligase is a member of the “E3 ligase” family, and its function is to bind 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 five hundred to a thousand known E3 ligases, and they are like recycling volunteers in the cells, responsible for tagging unwanted things and breaking them down.