I can't remember what I just said, I can't remember what I just did, I can't recognize the people who are with me... As one of the most difficult diseases in the world to cure, Alzheimer's disease is known as the "eraser in the mind".
The data shows that there are already more than 50 million Alzheimer's patients worldwide in 2021. Epidemiological investigations have shown that the number of women with Alzheimer's disease is twice that of men, but the cause of this phenomenon has not been clear before.
On March 3, Beijing time, the latest research results of Ye Keqiang's team, Chair Professor of the School of Life and Health of the Shenzhen Institute of Science and Technology (tentative name, referred to as "Shenzhen Polytechnic") of the Chinese Academy of Sciences, and the institute of brain cognition and brain diseases of the Shenzhen Institute of Advanced Technology of the Chinese Academy of Sciences, were published in Nature, revealing for the first time that the increase in follicle-Stimulating Hormone (FSH) is an important reason why women are more likely to suffer from Alzheimer's disease than men.
"This important finding not only provides new causes and mechanisms for answering why women are more likely to develop Alzheimer's disease, but also provides new molecular targets for early clinical screening and intervention in Alzheimer's disease." Wang Jianzhi, a professor in the Department of Pathophysiology of Tongji Medical College of Huazhong University of Science and Technology, commented.
Screenshot of the paper online.
Women are more susceptible to disease after menopause
Why are women more likely to develop Alzheimer's disease? Scientists have given various possible reasons for this problem.
Some people think that lack of sleep, long-term stress, etc. may be the cause of the high incidence of Alzheimer's disease in women; some people suggest that women with specific risk genes such as the ApoE 4 gene have a higher risk of developing Alzheimer's disease; and others think that this is related to the reduction of hormones after menopause in women, but there is no substantial evidence to know the exact cause.
Ye Keqiang's team has been committed to the study of the pathogenesis, early diagnosis and drug development of neurodegenerative diseases. Based on the systematic summary of the team's hundreds of cutting-edge academic papers, Ye Keqiang's team proposed a research theory that "there is a 'C/EBPβ/AEP neural signaling pathway' in the brain, and the activation of this pathway is the core driving factor leading to neurodegenerative diseases".
Based on this conclusion, the research team studied hormone substances that vary sharply in concentrations in women before and after menopause, and found in more than a dozen core hormones that have undergone important changes that follicle-stimulating hormone is an important causative factor that makes women more susceptible to Alzheimer's disease.
Studies have shown that after menopause, the content of follicle-stimulating hormone in women's bodies will increase sharply to 10 times to dozens of times, while the follicle-stimulating hormone in elderly men of the same age will only increase by 2 to 3 times. A sharply elevated follicle-stimulating hormone that binds to receptors on the surface of neurons in the brain activates the C/EBPβ/AEP pathway in the brain, leading to the production of Alzheimer's disease.
For women, follicle-stimulating hormone plays a role in promoting follicle development and maturation, participating in the formation of normal menstruation, and its production is also reverse-regulated by ovarian estrogen.
"During a woman's menstruation, estrogen rises and inhibits the increase of follicle-stimulating hormone through brain regulation, thus circulating. With age, ovarian function declines, women after menopause, estrogen decreases, follicle stimulators are no longer suppressed, resulting in women more susceptible to Alzheimer's disease. The co-first author of the paper, the former Ye Keqiang team Bo hou, now deputy chief physician of the Department of Neurology of Wuhan University People's Hospital Xiong Jing said.
Explore another path to explore the pathogenic mechanism
As an age-dependent neurodegenerative disease, Alzheimer's disease is mainly caused in the elderly, accompanied by symptoms such as cognitive impairment, memory imbalance and behavioral abnormalities, and its related pathogenesis is still unclear.
Previously, Ye Keqiang's team revealed that the CCAAT enhancer binding protein β (C/EBPβ) plays a key role in the pathogenesis of Alzheimer's disease by increasing the expression of asparagine endopeptase (AEP), and further proposed that activating the C/EBPβ/AEP signaling pathway can mediate lesions in Alzheimer's disease, a review article published in 2020 in Expertal & Molecular Medicine. Translational Neurodegeneration。
Since follicle-stimulating hormone is an important factor in women's greater susceptibility to Alzheimer's disease, how does it affect this signaling pathway and, in turn, the production of Alzheimer's disease?
To verify the accuracy, the research team conducted experiments from four different angles and approaches.
The team first injected follicle-stimulating hormone into a mouse model of Alzheimer's disease and found that both male and female mice accelerated the formation of changes in Alzheimer's disease-related pathologies. They then reduced pathological changes in ovariectomy mice by inhibiting the C/EBPβ/AEP pathway in a mouse model of Alzheimer's disease.
Second, they knocked out receptors in alzheimer's mouse model neurons so that follicle-stimulating hormone could not bind to the receptor and thus could not activate the C/EBPβ/AEP pathway, which alleviated the pathological symptoms of Alzheimer's disease mice after ovarian removal and enhanced memory recovery. Further, they injected a specific antibody to follicle-stimulating hormone intraperitoneally into Alzheimer's mice that had their ovaries removed, and found that after blocking the function of follicle-stimulating hormone, the C/EBPβ/AEP pathway could not be effectively activated, reducing the pathological behavior of the mice and restoring cognitive levels to a certain extent.
Focusing on the key factor of follicle-stimulating hormone, the research team fully confirmed that follicle-stimulating hormone leads to changes in Alzheimer's disease-related pathology through C/EBPβ/AEP pathways, from multiple links such as receptor gene knockout, specific blocking of follicle-stimulating hormone, exogenous supplementation, and inhibition of signaling pathways, further revealing the specific mechanism by which the incidence of Alzheimer's disease in women is higher than that in men.
Bring new treatment strategies to reduce the risk of disease
At present, the traditional methods of clinical intervention in Alzheimer's disease include drug intervention, genetic intervention, rehabilitation training, etc., but they can only improve symptoms, but they cannot prevent the development of the disease.
Faced with a higher risk of disease, how can women reduce the incidence of Alzheimer's disease?
In this regard, Ye Keqiang, the corresponding author of the paper, said that a balanced diet, maintaining an optimistic attitude, avoiding excessive stress, reasonable exercise, and ensuring adequate sleep time and quality can help reduce inflammation in the body, appropriately delay the arrival of menopause, and delay the occurrence of diseases to a certain extent.
It is understood that the next step of the research team will be to conduct a mechanism-level in-depth study of the relationship between specific risk genes such as ApoE4 and follicle-stimulating hormone to explain why female carriers of ApoE4 are more likely to be sick. In addition, the team's specific antibodies against follicle-stimulating hormone are being studied preclinically in hopes of bringing new treatment strategies to Alzheimer's disease.
"Our extensive previous research suggests that the C/EBPβ/AEP signaling pathway is a central factor and major contradiction in age-dependent diseases, and around this hypothesis, we hope to reveal how a wide variety of risk factors mediate the onset of neurodegenerative diseases by activating this pathway." Ye Keqiang said.
At present, Ye Keqiang's team is in the new laboratory of Deep Science and Technology, focusing on a variety of age-dependent chronic diseases such as diabetes, atherosclerosis, cancer and aging.
Wang Yanjiang, a professor of neurology at Daping Hospital of the Army Military Medical University, said that this study not only reveals a key reason for the occurrence of Alzheimer's disease in women after menopause, but also suggests that follicle-stimulating hormone is a common intervention target for common diseases of the elderly such as Alzheimer's disease, obesity, osteoporosis and hypercholesterolemia in the elderly. The use of antibodies and other methods to reduce follicle-stimulating hormone levels may be a new way to prevent and treat the above-mentioned diseases of the elderly and improve the overall health of the elderly, which is worth exploring in the future.
[Reporter] Ma Fang
【Author】 Ma Fang
【Source】 Southern Press Media Group South + client
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