阿尔茨海默 z-bo 2020-12-17 339

　　Alzheimer's disease is a devastating disease. At present, more than 5 million Americans have lost cognitive and memory functions because of this. Scientists have always been puzzled by the root cause of the disease. But in a controversial editorial that will be published in the Journal of Alzheimer's Disease, a group of scientists suggested that the cause of this complex disease may be simple: it is something that can cause the brain. Ministry of infection by microorganisms. This controversial view is not new. For a long time, academics have considered it too absurd and ignored it. However, more and more work has pointed out that this may be a direction worthy of consideration and further research. If researchers can prove this theory and explain some of the details that have previously sparked controversy (both tasks are difficult, because the research on brain infections is so difficult), then people can fundamentally prevent the disease happened. This editorial, jointly published by 31 scientists around the world, believes that in certain susceptible populations—for example, individuals with mutations in the APOE ε4 gene (the mutation is a known risk factor for Alzheimer’s disease)— Common microbial infections can invade the aging brain and cause damage to its function. These microorganisms may include herpes simplex virus 1 (HSV-1), a common virus that causes cold sores, and Chlamydophila pneumoniae and Borrelia burgdorferi, which can cause Pneumonia and Lyme disease. This controversial idea runs counter to the mainstream theory. It has always been believed that amyloid-beta proteins and tau tangles formed by Tau proteins accumulate in the brains of Alzheimer’s patients. It is the main cause of cell death caused by this disease. The proponents of the so-called "pathogen hypothesis" believe that either pathogenic microorganisms induce brain cells to produce amyloid and neurofibrillary tangles, or nerve cells damaged by infection produce them during the immune response to pathogens. Co-author of the editorial, Brian Balin, is the director of the Center for Chronic Disorders of Aging (Philadelphia College of Osteopathic Medicine). He said, "We admit that the phenomenon described by the amyloid theory does exist, but this is a follow-up reaction secondary to the initial infection." Critics of the "pathogen hypothesis" pointed out that many human studies supporting this theory have not established a causal relationship between the pathogen and Alzheimer's disease. Ruth Itzhaki is a molecular neuroscientist at the University of Manchester, UK. His team reported a phenomenon in a study published in The Lancet in 1997 ——For people who are infected with the HSV-1 virus while containing the APOE ε4 gene mutation, the probability of them suffering from Alzheimer's disease is higher than that of people who have this gene mutation alone or are infected with HSV-1 alone. 12 times as much. There is a hypothesis that APOE ε4 mutation makes HSV-1 more likely to infect the brain-but critics believe that it is also possible that such genetic mutations and infections are related to Alzheimer's disease, but there is no cause and effect between them. relationship.

　　 Scientists have also tried to use animal experiments to confirm this hypothesis. For example, researchers in Spain have found that when the rat brain is infected with HSV-1, the rat containing the APOE ε4 mutation produces 14 times the viral DNA of the normal rat. When HSV-1 infected the brains of rats, Itzhaki's team found that their brains accumulated amyloid. But these studies have also been criticized-after all, what happens in the brain of a mouse does not necessarily happen in the human brain.

　　 Proving this hypothesis is a very difficult task, partly because it is almost impossible to detect virus infections like HSV-1 in the brain of a living person—they can only be found during an autopsy. "Proving the causality is a major, critical and very complex issue," said David Relman, an infectious disease expert at Stanford University. Itzhaki agreed with this view, pointing out that people cannot simply inject the virus into a living person and see if they develop Alzheimer's disease. (Australian microbiologist Barry Marshall once inoculated the pathogen into his body, and finally confirmed that Helicobacter pylori is indeed the culprit that causes gastric ulcers, quelling people's doubts.) Itzhaki said that a potential solution is to conduct clinical trials. , Use antiviral drugs to treat patients with mild Alzheimer's disease who are infected with HSV-1 and carry the APOE ε4 mutation, and evaluate whether their condition has improved. They have proved through experiments that these antiviral drugs can inhibit the formation of amyloid plaques in cells infected with HSV-1. She has also submitted numerous funding applications for human research, but has not been successful so far.

　　 Rudolph Ranzi is a neuroscientist at Harvard University and the leader of the Genetics and Aging Research Unit at Massachusetts General Hospital. He also believes that microorganisms may play a role in the occurrence and development of Alzheimer's disease, but his research shows that the brain's response to infection may be more dangerous than the infection itself. Ranzi reminds people, "We do need to seriously consider the role of microorganisms in brain diseases, but this is an extremely complicated thing, rather than just saying'infection causes Alzheimer's disease.'" (He is not here. Authors of this editorial.) In a 2010 study, Tanzi and his colleagues reported a phenomenon: Amyloid strongly inhibits the growth of microorganisms in the brain, which may mean that its accumulation is the brain’s infection Kind of response. He explained: "In the five years after the 2010 article was published, in every Alzheimer model we tested (from cells, flies, dirty worms to rats), β-starch Such proteins play an important role in the fight against infection." He said that even if only a few microorganisms invade the brain, they can trigger the accumulation of the protein.

　　 Infection can also induce a strong immune response, and this seems to make this problem even more difficult. Normally, a type of immune cell called microglia in the brain can eliminate amyloid. But when the body responds to infection, it will “activate” these cells, and their “daily clearance” will no longer proceed, causing amyloid to increase at a faster rate. As Tanzi's team showed in a 2014 nature article, amyloid that fills the brain stimulates the formation of neurofibrillary tangles, which can cause more brain cell death. "At this time, the disease has entered its heyday," Tanzi said.

　　 On the question of which pathogen may trigger Alzheimer's disease, Tanzi believes that HSV-1 is an alternative answer, but it is too early to make a conclusion. "I think we should look back a few steps, for example,'Which kind of bacteria, viruses or fungi will continue to accumulate in the brain as we get older?' And we should take an objective and skeptical attitude to systematically Investigate this issue," he said. Tanzi is now leading a group funded by the Cure Alzheimer's Fund (the foundation is a non-profit organization) that intends to match the microbiome in the human brain; he believes that once Discovery of potentially important microorganisms, then it is possible to develop neuroimaging techniques in the living human brain to track them.

　　 Even so, other scientists in the field of Alzheimer's disease are still not fully convinced. David Holtzman is the chairman of the Department of Neurology at Washington University School of Medicine (St. Louis) and the Knight Alzheimer's Disease Research Center under the institution. )'S deputy supervisor. He told the "Scientific American" magazine that although we need more research on this idea, "but now there is no obvious or conclusive evidence to prove whether or to what extent different types of infections can affect people. The risk of Alzheimer's disease." Tanzi said that when he presented his ideas or discoveries at a scientific conference, the reactions of the participants were indeed mixed. Among them, a view often heard by Itzhaki is that if HSV-1 can be found in the brains of healthy elderly people, and in fact it is true, then it cannot be considered that the virus can cause Alzheimer's disease. But she pointed out that some other pathogens, including Mycobacterium tuberculosis, can only cause symptoms of infection in some susceptible people. If we finally discover that microorganisms are indeed a potential cause of Alzheimer's disease-and for most researchers, this is really just "if"-then the effect of this discovery will be very huge : We may only need to inject vaccines to prevent annoying infections, and then we can prevent the occurrence of this terrible disease. At the very least, doctors can control infections with antimicrobial drugs before they cause damage to the brain. However, it may take decades to accumulate sufficient proof for this hypothesis. As for the other challenges, the funding problem is most criticized by researchers. Itzhaki said, "I have done this work for more than 50 years, and the entire team has almost always faced extremely difficult funding problems-our funds are too small."

　　 However, considering that many clinical trials of Alzheimer's disease drugs based on mainstream theories have failed, those researchers working on various "pathogen hypotheses" believe that it makes sense to continue this theory. Most importantly, they hope that this editorial will at least enable skeptics to consider the possibility of microorganisms playing a role in Alzheimer's disease and support them in further research. Balin said: "We just want to say,'Wait, man-we have a lot of evidence accumulated from decades of work that needs people to look at it carefully."