Amyloids are not always bad?
Stanford scientists turn the dogma "amyloid is bad" upside down
LifeSciencesToday based on Stanford School of Medicine:
Accused of complicity in Alzheimer’s, amyloid proteins may be getting a bad rap, study findsAmyloids, which form clusters of improperly folded proteins found in the brains of patients suffering from Alzheimer's disease and other neurodegenerative diseases, are considered terribly "bad guys" in neuroscience, disrupting the normal function of neurons responsible for memory and movement, and scientists around the world have spent decades trying to learn how to block their synthesis and accumulation in the human body.
But scientists at the Stanford University School of Medicine have taken a firm course to restore the reputation of these proteins that form the so-called amyloid plaques. It looks like they're going to turn the whole neuroscience upside down.
The first study, published in August last year, showed that one of the amyloid–forming proteins - beta–amyloid, directly linked by scientists to the development of Alzheimer's disease, can reverse the symptoms of a neurodegenerative disease in laboratory mice, close to human multiple sclerosis.
The second study (Kurnellas et al., Amyloid Fibrils Composed of Hexameric Peptides Attenuate Neuroinflammation), published in April this year in the journal Science Translational Medicine, showed that small fragments of several amyloid-forming proteins (including the well–known "criminals" - tau protein and prions) can also quickly alleviate symptoms in mice with this disease – despite the fact that they can and form long fibrils, previously considered to have a negative effect on neurons.
"We found that, at least under certain circumstances, amyloid peptides actually help the brain," says study leader Lawrence Steinman, MD, professor of the Departments of Neurology and Neurobiology and Pediatrics. "This really turns the dogma of "amyloid is bad" upside down. This will require changes in fundamental ideas about neurodegeneration and diseases such as multiple sclerosis, Alzheimer's disease and Parkinson's disease."
Professor Steinman is a well–known expert in the field of multiple sclerosis, whose research led to the development of natalizumab (Tysabri, Tysabri) – a powerful drug for the treatment of this disease.
Taken together, these two studies are the first step towards a radically new idea that full–sized amyloid-forming proteins can actually be produced by the body as a protective, rather than a destructive factor. In particular, Professor Steinman's research shows that these proteins can function as molecular chaperones that accompany and remove specific molecules involved in the development of inflammation and inadequate immune responses from the damage zone.
Although the results of these two studies can be called surprising, certain assumptions that amyloid-forming proteins play not only a negative role were expressed in earlier articles by other scientists. In particular, inhibition, or knockout, of the expression of several proteins in mouse models of multiple sclerosis – a pathway that should block the progress of the disease if these proteins are indeed its cause – on the contrary, led to an aggravation of symptoms.
There is no denying the fact that these amyloid-forming molecules, which are considered dangerous, are surprisingly widespread. "We know that the body produces a lot of amyloid-forming proteins in response to damage," says Professor Steinman. "I doubt that this is done to cause even more harm to the body. For example, prion protein is present in every cell of our body. What is its function? It is quite possible that any therapeutic effect aimed at removing all these proteins may interfere with their natural function."
Scheme of formation of beta-amyloid plaques. (Fig. comerbemateaos100.blogspot.ru)
Understanding how amyloids are formed requires understanding the biology of proteins, which are essentially chains consisting of smaller components – amino acids –connected to each other end to end. To perform their function in the cell, immediately after formation, these amino acid chains are folded into certain three-dimensional structures that correspond to each other, like keys and locks.
An improperly folded protein is obviously unable to perform its functions and must be disposed of by the body's cellular system, which controls the excretion of biochemical waste. However, amyloid-forming proteins (of which there are about 20) are poorly excreted, if they are excreted at all. Instead, they initiate a chain reaction with other misfolded proteins, forming long insoluble chains called fibrils that bind to each other to form amyloid clusters. These clots are invariably present in the brains of patients with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and multiple sclerosis, but not in the brains of healthy people.
Although amyloid clusters are considered harmful to nerve cells, the exact mechanism of causing this harm remains unclear. One of the possible variants of an unfavorable development of events may be based on the ability of fibrils to form cylindrical pores that violate the integrity of the cell membrane and the ordered flow of ions and molecules used by cells for communication and transmission of nerve signals. Nevertheless, their very presence testifies to the diagnosis of neurodegeneration for many doctors. Until recently, Professor Steinman was among such doctors.
"We started this study because such molecules are present in the brains of people with multiple sclerosis," says Steinman. "We hoped to show that the presence of beta-amyloid worsens the condition of laboratory animals. Instead, we saw that they bring great benefits."
Intrigued by the results of their first study, the scientists tested the effect of small, consisting of six amino acids, fragments of several amyloid-forming proteins, including beta-amyloid, with approximately the same three-dimensional structure. They found that almost all of these tiny protein molecules, or hexamers, could also temporarily reverse the symptoms of multiple sclerosis in mice (after stopping treatment, signs of the disease appeared in animals for several days).
The researchers noticed that the therapeutic effect of hexamers was related to their ability to form fibrils similar to their longer parent molecules, but not identical to them. For example, these simplified hexameric fibrils form and disintegrate more easily than those consisting of whole proteins. In addition, they do not appear to be able to form cylindrical pores capable of damaging cell membranes. Finally, hexamer fibrils appear to inhibit the formation of fibrils from full-sized proteins – possibly by blocking, or failing to stimulate, the chain reaction that initiates the formation of fibrils.
By mixing the hexamers forming fibrils with the blood plasma of three people with multiple sclerosis, the researchers found that the fibrils bind and remove from the solution many potentially dangerous molecules involved in the development of inflammation and immune response.
"These hexameric fibrils appear to work to remove dangerous chemicals from the damage area," says Professor Steinman.
Scientists plan to continue using small hexamers as a means of therapy for neurodegenerative diseases such as multiple sclerosis. Further research is needed, but Professor Steinman is hopeful.
"The lessons we learned from studying amyloid-forming proteins in multiple sclerosis may be useful for the treatment of stroke and brain injuries, as well as Alzheimer's disease," he says. "We get information about how today's therapeutic approaches can affect the body, and begin to understand the nuances necessary for the development of successful treatment methods. Although it will take time, we are determined to move our promising results from the laboratory to the clinic as soon as possible."
Portal "Eternal youth" http://vechnayamolodost.ru23.04.2013