Release date: 2017-08-09
If one day you suddenly discover that the person you thought was always going to kill you is actually protecting you, what do you think? Just like the first episode of Harry Potter, Professor Snape was in the Quidditch game to recite a spell for Harry Potter.
It now appears that the field of Alzheimer's disease is very likely to stage this scene.
In 1906, German doctor Alois Alzheimer found a strange brain in a woman who died of dementia. Her brain tissue was covered with plaques and entangled. [1] Since then, the disease has been named after the scientist, which is the famous Alzheimer's disease.
It was not until the 1960s that British scientist Martin Roth discovered that the degree of dementia was related to the degree of plaque and nerve entanglement. In 1984, scientists discovered beta amyloid in the brains of patients with Alzheimer's disease. Subsequently, the academic community established a link between beta amyloid and Alzheimer's disease. In 1988, Claude Wischik, who studied in the UK, isolated Tau protein from plaques in the brains of Alzheimer's patients, demonstrating for the first time that Tau protein may be the cause of dementia. [2]
Left: normal brain, middle: brain of patients with mild cognitive impairment, right: brain of Alzheimer's disease
However, in the past 30 years, mainstream academics have consistently maintained that "beta amyloid, which is concentrated in the brain, is the culprit in Alzheimer's disease." Their conclusions mainly come from the following three phenomena [3]: 1β amyloid metabolism-related gene mutation causes β-amyloid overproduction, leading to familial Alzheimer's disease; 2β amyloid gene is located on chromosome 21 , Trisomy 21, because of a copy of the amyloid beta gene, eventually leading to Alzheimer's disease-like pathological changes and cognitive impairment; a mutation in a site on the 3β amyloid gene can significantly reduce beta amyloid Protein production is associated with a decreased risk of developing Alzheimer's disease.
All of the above, let the "β amyloid hypothesis" become the focus of attention.
Based on this assumption, major pharmaceutical giants have invested billions of dollars in an attempt to develop drugs for the treatment of Alzheimer's disease. However, according to Adis R&D statistics (as shown in the figure below), between 1998 and 2015, major pharmaceutical companies launched a total of 123 drugs for the treatment of Alzheimer's disease [4], only three drugs plus one The combination treatment program has been approved by the FDA for marketing. However, without exception, none of the 123 drugs can cure Alzheimer's disease, and even delay the progression of the disease.
Alzheimer's disease drug development map from 1998 to 2014
Although Wall Street said that they are very confident about the "beta amyloid hypothesis." However, a group of people in the academic world have been suspicious of this "toxic protein accumulation hypothesis." After all, the beta amyloid is dry, and scientists know very little about it. Dr. Rudolph E. Tanzi and Dr. Robert D. Moir of the Massachusetts General Hospital of Harvard University are two of them.
Although the mainstream academics believe that beta amyloid is a "metabolized junk", there is no value in the brain; but Dr. Moir and Tanzi also see that beta amyloid has been present in the human body since about 400 million years ago. And 60% of vertebrates have traces of it, including fish, reptiles and birds. Moreover, it involves the response to environmental stress and the activation of inflammation in the body. They faintly feel that beta amyloid is very similar to the key anti-infective protein "antibacterial peptide" in the innate immune system (the body's first and oldest line of defense).
Left: Dr. Rudy Tanzi Right: Dr. Robert Moir
So they poured a lot of effort into this direction. In 2010, Dr. Moir and Dr. Tanzi were surprised to find that amyloid beta inhibits the growth of eight clinically common pathogens, and its antibacterial effect is comparable to that of human antimicrobial peptide LL-37, and even better on some pathogens. LL-37. Moir said that this bactericidal effect of amyloid beta is comparable to penicillin. [5]
At this time, Dr. Moir and Dr. Tanzi had a big question in their hearts: Isn't the murderous "murderer" gathered in large numbers just to protect us?
Next, they started a five-year study. Finally, in 2016, it was further proved that β-amyloid is indeed an antibacterial peptide, which can effectively prevent nematodes, mouse and human neuronal tissues from infecting fungi and bacteria. The work also found that when they took the plaque from the brain of the mouse, a closer look showed that there was a microbe in the center of the plaque. This makes the singular cake think of the formation of "pearl". Last year, their important research was published in the famous journal Science Translational Medicine. [6]
Comparison of amyloid and LL-37 inhibition
In fact, for a long time in history, scientists believe that the brain is sterile due to the existence of structures such as the blood-brain barrier. Dr. Tanzi said in an interview with Forbes, "We now know that the brain is not sterile, there are bacteria, viruses and fungi, and there are bigger parasites, such as scientists even found nematodes in the brain. Because with age Growth, our blood-brain barrier begins to collapse, and microbes begin to invade."
When the microbe invades, beta amyloid is immediately activated. It immediately fought back and tried to stop the "enemy" from approaching the brain cells. Beta amyloid first binds the invader into a ball and then forms a fiber to form a net. The web forms a plaque that buryes these microbes so that they cannot get close to and infect brain cells.
In the view of Dr. Moir and Tanzi, the aggregated amyloid plaques eventually lead to inflammation and nerve cell death, but they are really unintentional and there is no way. Because for decades, drugs that lower the beta amyloid content of the brain have not alleviated Alzheimer's disease. In addition, in their 2016 study, they found that mouse brains form beta amyloid plaques 48 hours after infection with Salmonella. It is important that these mice are smaller than those that do not form beta amyloid plaques. The mouse live longer.
Based on these studies, Dr. Moir and Dr. Tanzi boldly proposed their understanding of Alzheimer's disease and beta amyloid. They believe that beta amyloid induced by viruses, bacteria and fungi is an immune stress response after brain infection. Beta amyloid is a "savior" in the brain tissue of the brain, not a "killer." It wraps viruses, bacteria, and fungi that invade the brain, and collects harmful pathogens into blocks to prevent them from infecting the brain. [7]
Response of β-amyloid to bacterial infection in mouse brain slices - Image courtesy of Dr. Mior
According to Dr. Moir and Dr. Tanzi's hypothesis, researchers need to figure out which pathogens are invading, leading to the brain producing beta-amyloid antibacterial peptides. If we can find this pathogen and then kill the pathogen in a targeted manner, it is possible to cure Alzheimer's disease. This completely opened up a whole new direction for the study of Alzheimer's disease.
Currently, the Cure Alzheimer's Fund and the Good Ventures Foundation are fully supporting the research work of Dr. Moir and Dr. Tanzi. With the strong support of these two institutions, Dr. Moir and Dr. Tanzi are working on an ambitious Brain Microbiome Project. This research project will likely unravel the mystery of beta amyloid.
Reference materials:
. [1] H.-J M llerM B. Graeber 1998. The case described by Alois Alzheimer in 1911. European Archives of Psychiatry and Clinical Neurosciences (1998) 248:?.. 111.
. [2] Wischik CM, Novak M, Edwards PC, Klug A, Tichelaar W, Crowther RA 1988. Structural characterization of the core of the paired helical filament of Alzheimer disease Proceedings of the National Academy of Sciences 85:. 4884-8
[3] Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. 2015. Alzheimer's disease. Nature Reviews Disease Primers:15056
[4]Movement AsI. 2015. Researching Alzheimer's Medicines: Setbacks and Stepping Stones Summer 2015. PhMRA
[5] Soscia, S. J., Kirby, J. E., Washicosky, K. J., Tucker, S. M., Ingelsson, M., Hyman, B., ... & Moir, R. D. (2010). The Alzheimer's disease-associated amyloid β-protein is an antimicrobial peptide. PloS one, 5(3), e9505.
[6] Kumar, D. K. V., Choi, S. H., Washicosky, K. J., Eimer, W. A., Tucker, S., Ghofrani, J., ... & Moir, R. D. (2016). Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Science translational medicine, 8 (340), 340ra72-340ra72.
[7] Jefferson, R. S. 2017. Mapping The Brain's Microbiome: Can Studying Germs In The Brain Lead To A Cure For Alzheimer's?
Source: Singularity Network
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