Alzheimer: severity beyond expectation
Alzheimer's disease (AD) is severe. People with AD suffer from progressive nervous system degeneration, characterized by memory impairment, aphasia, apraxia, agnosia, visuospatial skills impairment, executive dysfunction, personality and behavior changes, and other comprehensive dementia manifestations (Gauthier S, 2022). From our interview with Professor Chen, We learned that late-stage AD patients would have significant problems during daily life like memory loss and inability to conduct daily actions. Therefore, we genuinely want to do some things to contribute to the treatment of Alzheimer's Disease.
At present, the incidence of AD is very high. There are about 10 million AD patients in China, the number of the world's largest. It is expected that by 2050, more than 40 million people in China will suffer from AD. In the United States, one in three older people dies from AD or other types of dementia, already more than breast and prostate cancer combined. More importantly, as the population's age and life expectancy increase, the prevalence of AD and the number of deaths from it increased significantly in recent years since a more significant percentage of the population is now in the highest risk age range. Based on the '2022 Alzheimer's Disease Facts and Figures report by the Alzheimer's Association, about 1 in 9 people (10.7%) over age 65 has Alzheimer's dementia. In 2022 in the U.S, an estimated 6.5 million people 65 years and older have Alzheimer's disease, with 73% being 75 and older. By 2050, the Alzheimer's Association expects a significant increase in Americans age 65 and older to have Alzheimer's Disease, estimating approximately 12.7 million people. Between 2000 and 2019, deaths from stroke, heart disease, and HIV decreased, whereas reported deaths from AD increased by more than 145%. The U.S. Annual Alzheimer's Death Rate (per 100,000 People) by Year has risen from 17.6% to 37.0% from 2000 to 2019 (Alz.org. 2022. 2022 Alzheimer's Disease Facts and Figures). AD has become a significant killer threatening human health and life.
Our solution
However, up to now, there is no specific drug for AD treatment, which means AD is still an incurable disease. We have done much human practice work in this regard, finding that only six related drugs were on the market in 2020 and that none of these drugs could achieve the theoretical effect. In this field, we also interviewed experts, the MUC (Minzu University of China) neurobiology Prof. Hu told us that the human central nervous system is surrounded by the "blood-brain barrier," a structure that provides a protective effect. However, at the same time, it blocks many drugs into the brain, so these drugs do not work as well as they do in vitro studies. In this investigation, we found that metabolites named astragalin could cross the blood-brain barrier after ingestion, and this could effectively alleviate the AD process. Therefore, we hope to produce an effective and cheap drug to help humans fight AD by using astragalin as the primary substance.
What is Astragalin?
Astragalin is a natural flavonoid compound in medicinal plants like Cuscuta Chinensis. It has significant functions in anti-inflammatory, antioxidant, cardiotonic, analgesic, antibacterial, anti-allergic, and anti-hepatotoxic effects. It can repair damaged DNA and inhibit the generation of TNF-α, IL-1β, and IL-6.
Disadvantages of the traditional extraction methods
At present, people mainly produce astragalin through the chemical synthesis method. Through our human practice, we have found that this approach is very costly; the current price is 900RMB for every 20mg; Besides, the chemical synthesis method also wastes more organic solvents, causes more harm to the environment, and has a complex process that takes a relatively long time.
Improvement
Synthetic biology, which has emerged in recent years, can use natural organisms and enzymes to produce various chemical substances that are environmentally friendly. The cost of cultivation can also be effectively controlled by selecting good substrate organisms. Therefore, we plan to use synthetic biology methods to produce astragalin cheaply and environmentally friendly for AD-related drug development and other related applications.
After reading papers, we found that plants can convert naringenin into astragalin through F3H, FLS, and UGT enzymes. Due to the high cost of plant tissue culture, we plan to introduce the above enzymes into the chassis at lower price, firstly, we chose E. coli, and the alternative is yeast, and test whether naringenin can be converted into astragalin. According to our experiment results, E. coli has a prominently higher efficiency in enzyme synthesizing, so we chose E. coli as our chassis organism. Subsequently, we tried to improve the yield of astragalin and reduce the generations of by-products by modifying E.coli and optimizing the culture conditions. Finally, we used plasmid pETDuet-1 in E. coli forand extracted astragalin from those microorganisms. Furthermore, astragalin can be safely absorbed by the body through the Gastrointestinal tract; the public also prefers oral medicine. In the future, we plan to design this astragalin into an oral drug to treat AD.
Reference
Gauthier S, Webster C, Servaes S, Morais JA, Rosa-Neto P. 2022. World Alzheimer Report 2022: Life after diagnosis: Navigating treatment, care and support. London, England: Alzheimer's Disease International.
Alz.org. 2022. 2022 Alzheimer's Disease Facts and Figures. [online] Available at: