The dilemma and way out of Alzheimer's disease
April 18, 2019 Source: Science and Technology Daily
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];After the episode of "It's Very Good", Alzheimer's disease (hereinafter referred to as AD) has once again entered the public eye. However, its occurrence and development in medicine is still a mystery. When it is believed that the deposition of beta amyloid causes neuronal damage to be the culprit, the giant drug companies that have been developing drugs for many years have had to declare that all efforts to enter phase III clinical trials have failed.
In the process of human research on AD, many times thought that the vitality of the "disappearance", but only the meteor in the long night. Recently, the 647th academic seminar of the Xiangshan Science Conference was held with the theme of "Biology and Clinical Intervention of Aging and Neurodegeneration". Professor Shen Yong from the Center for Neurodegenerative Diseases of the University of Science and Technology of China said that it is currently ok. The causal relationship is that aging is the biggest risk factor for neurodegenerative diseases, and the greater the age, the greater the likelihood of illness.
The data show that about 10% of people in the 65-year-old population are sick, while about 50% of the 85-year-old population is sick. "AD patients have impaired memory as the first symptom, which suggests early involvement of the hippocampus, which in turn leads to multiple cognitive damage, suggesting a wider range of cortical damage," said Professor Cui Liying, director of the Department of Neurology at Peking Union Medical College Hospital.
With the rapid aging of our society, the incidence of AD will become higher and higher. In addition to reflecting the inconsistency of the contradictions of the original family, "It's quite good" is also a wake-up call for the hidden worry that China is about to enter the old society. Therefore, the decryption of the AD mechanism is imminent.
Exploring the hardships: I think that the difference is a thousand miles.
On November 23, 2016, the giant pharmaceutical company Lilly Company announced that its new AD drug Solanezumab did not reach the clinical primary endpoint in the phase III trial and the trial failed. In the following 2017 and 2018, Merck and Pfizer of the United States also announced the failure of new drug development for AD.
"AD treatment studies for beta amyloid (sediments in the brain of AD patients) have been the result of failure in the last 20-30 years." Cui Liying said that AD is still an exploration of potential neurodegenerative diseases. Treatment target.
Failed drug development uses the accumulation of harmful proteins as the cause of AD. The study found that a variety of misfolded proteins are found in the nervous system of AD patients, which in turn constitute an insoluble polymer and suffer from AD. In the past, it was thought that eliminating these proteins would restore cognition.
Therefore, people taking these proteins as targets, and reducing the protein can alleviate the symptoms of AD. However, the effective drugs in cells and animals have poor data on the human body. The results of the giant's long-term, large-capacity clinical study showed that there was no significant difference between the experimental drug group and the placebo group.
Why is this happening? People began to suspect that the protein deposition hypothesis may not be perfect, and some people criticized the hypothesis, which was not confirmed in the mechanism theory, and thus gave the wrong guidance.
The unclear mechanism makes some conclusions that seem to be only a few milliseconds. "In the case of both nematodes and yeast, it is clear that the excessive expression of Sir2 will delay aging." Zhu Bing, a researcher at the Institute of Biophysics, Chinese Academy of Sciences, said that Sir2 and its homologues have been extended to the model life cycle, and the human body has become an academic consensus. Sir2 in is a human source SIRT1. theory
In the above, the source of SIRT1 is produced more, which can resist aging and reduce the complications of aging such as AD.
“Harvard professor David Sinclair discovered that resveratrol is effective in promoting the deacetylase activity of SIRT1 in vivo and in vitro to delay aging, and established a biotechnology company to sell it for $700 million. Zhu Bing said, but after taking over the company one year later, he gave up the high-selling "hot potato". Before and after the storm, resveratrol was highly hyped, and it is still known as anthocyanin and collagen, and is called the three mountains of oral anti-aging.
Finally, the research team of the Institute of Biophysics of the Chinese Academy of Sciences, Xu Ruiming, used a method of structural biology to reveal that the deacetylase SIRT1 and the agonist resveratrol emitted a "one-shot light" because of its fluorescence for detection. The modified group has made a third party with the “Lang Langâ€. Xu Ruiming solved the protein structure, and the results speak for themselves. Resveratrol was invited to the "Altar".
Bypass breakthrough: cerebral infarction may be closely related to dementia
“In recent years, clinical trials have shown that breakthroughs have not been made in targeting single drug therapy. This suggests that our single goal and single treatment are not suitable for dementia.†Wang Yongjun, deputy dean of Beijing Tiantan Hospital and director of the Center for Neurology, Capital Medical University The professor believes that the treatment of AD should consider the comprehensive factors of its disease.
"Recent studies suggest a strong correlation between vascular disease and dementia." Wang Yongjun said that Oxford vascular research also suggests that a history of stroke and increased stroke severity significantly increase the risk of dementia. In addition, a series of studies from the United States and Canada have shown that vascular factors play an important role in the occurrence of dementia.
The results of several epidemiological and pathological studies point to this conclusion. Cui Liying agrees that the role of vascular factors in the development of dementia may be the result of a multi-channel effect. In addition to cerebrovascular disease, which may cause vascular brain structural damage, it may also cause damage to the nerve circuit due to hypoperfusion white matter damage. Cortical neuron apoptosis.
"The neurovascular unit is affected by the combined effects of dementia, stroke, metabolism, and immune functional biology, and a multidisciplinary approach is needed to comprehensively understand the mechanism between vascular biology and cognition." Wang Yongjun emphasized that vascular risk factors, small blood vessels The interaction between disease and amyloid constitutes the pathological mechanism of AD.
The occurrence of AD is likely to be a "domino" with interlocking and multiple pathways. "The initial stage of AD is mainly the changes of cerebral vascular structure, cerebral hemodynamic changes, blood-brain barrier disease destruction; followed by brain structure and network changes caused by cerebral small vessel disease." Wang Yongjun explained, AD and blood vessels On the one hand, vascular damage, blood-brain barrier destruction and other cognitive disorders; on the other hand, can stimulate and accelerate the process of neurodegeneration.
These paths end up pointing to AD, but people are likely to only know the minutiae in the roadmap, or individual nodes, and how the overall condescency is still unknown.
At present, some trials have shown that nimodipine can not improve the cognitive ability of patients with acute ischemic stroke with vascular cognitive impairment. "The results of these studies provide us with a new direction to explore prevention of AD." Wang Yongjun said.
The new mechanism is now dawning: it is still because the fruit is still unknown.
Studies have shown that there are abnormally high levels of inflammatory factors and their associated immunoinflammatory markers in the brains of AD patients. "But it is still unclear whether the inflammatory factor is because of the AD's disease, the body's defense, or the cause of AD." An expert said that there are also studies to try to remove inflammatory factors to see if it can improve cognitive function. .
In the field of new AD drugs, China issued a good voice in June 2018. The new AD drug "Gal oligosaccharide diacid (GV-971) was jointly developed by China Ocean University, Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Shanghai Lugu Pharmaceutical. "The clinical phase III trial was successfully completed in the month. The drug was accepted by the State Drug Administration in November of that year.
According to Professor Geng Meiyu, the inventor of GV-971, the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, GV-971 has a unique mechanism of anti-AD action. In addition to inhibiting amyloid-like protein, it can also reduce the inflammatory response in the brain by regulating intestinal flora. The preparation can target multiple links of AD onset, and multiple targets can work together to focus on both the focus and the overall situation.
According to the 2018 report of the International AD Association, there are currently about 50 million AD patients worldwide, which will reach 152 million in 2050. The AD Association of the United States predicts that if a new drug is available that targets multiple possible causes, changes the course of AD, and improves symptoms, it can reduce severe AD cases by 50% in the next 5 years and 80% in 2050.
Although the mechanism of the pathogenesis of AD is still uncertain, it is increasingly clear that the cure for AD will not be "single-threaded" but should be a "generalist."
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