Human antibodies against the pathogenic protein that causes Alzheimer's disease destroy dangerous protein deposits in the brains of patients.
Alzheimer's disease, like other neurodegenerative diseases, begins due to the fact that in the nerve cells of the brain there are too many protein molecules in the wrong spatial conformation, which, due to their irregularity, stick together and form insoluble complexes that harm the neuron and, ultimately leading him to death. Not every protein is pathogenic; in the case of Alzheimer's disease, these are beta-amyloid and tau-protein, and one of the characteristic signs of the disease is the so-called amyloid plaques, accumulations of beta-amyloid peptides that appear in the patient's brain. It is not yet fully understood how exactly these proteins harm neurons, but it is certain that they do harm.
Brain tissue with alzheimer's plaques. (Photo by UCSF / Corbis.)
Alzheimer's plaques in the brain of a mouse. (Photo by Enrique T / Flickr.com.)
Obviously, drugs against neurodegenerative diseases should, on the one hand, suppress the appearance of pathogenic proteins and their interaction with each other, on the other, destroy already formed deposits, that is, those notorious plaques. Many people here rely on immunotherapy: antibodies that specifically bind to beta-amyloid molecules could prevent them from sticking together and provoke the destruction of already formed amyloid deposits. However, for the time being, there were no special breakthroughs here: immunotherapeutic methods gave, at best, only a very moderate effect. But with antibodies obtained by employees of the biotech company Biogen, Inc. , things are completely different.
As you know, antibodies are synthesized by B-lymphocytes. Jeff Sevigny ( Jeff sevigny) and his colleagues found among human B-lymphocytes those that produce immunoglobulins against beta-amyloid peptide - the preparation of such antibodies was called aducanumab. Experiments with transgenic mice, in which deposits of human amyloid were formed in the brain, showed that antibodies introduced into the blood penetrate into the brains of animals, bind to filamentous amyloid accumulations, transforming them into a soluble state, and activate microglial cells, which are the brain part of the immune systems. (Normal immune cells wandering around our body cannot enter the brain.) The activated microglia literally begin to absorb amyloids, which have become soluble thanks to the adjyukanumab drug.
But these are animals, besides, transgenic, but what about people? To participate in clinical trials, 165 patients were invited, aged 50 to 90 years, in whom Alzheimer's syndrome was either present in a mild form, or was in the so-called prodromal period, when some symptoms already indicate the disease, but clinically it has not yet manifested itself. Some of the participants in the experiment received a placebo, while the other four groups used the antibody preparation at different concentrations. Immunoglobulins were injected once a month, and there were fourteen such injections. Along the way, forty patients dropped out of the study for various reasons, leaving between 21 and 32 people in each of the five groups. The state of the brain was assessed using positron emission tomography and a special radioactively labeled substance that settled in the amyloid deposits and thereby made them visible for a tomograph.
In general, as the authors of the work write in Nature, Alzheimer's plaques in humans have decreased markedly, and this decrease has even been called "unprecedented" - in comparison with other attempts of this kind. The disappearance of amyloid deposits was the more active, the higher the dose of the experimental drug was. Some cognitive tests showed that those who received the antibody drug did not weaken as quickly as those who received the placebo, and that again it was all dose-dependent. At the same time, it is worth noting that other tests did not find any cognitive differences. On the other hand, some specialists, in particular, Ronald Petersen ( Ronald Petersen) from the Mayo Clinic, say that while cognitive assessments are not too important, they take more subjects and more research time to make them reliable.
Now the next phase of clinical trials is underway, in which more people are participating. The researchers hope that they will be able not only to confirm the initial results, but also to understand what to do with the side effect, which was especially noticeable in some patients who received the highest dose of the drug - tomography showed that they had small swelling and microscopic hemorrhages leading to headaches. One of the explanations is that amyloid deposits sometimes form close to blood vessels, and when these deposits begin to pull away antibodies, the vessels react to their work somewhat painfully. But, we repeat, we would like to hope that in further clinical experiments the side effects can be overcome.
Old age and the buildup of amyloid beta-protein plaques in brain tissue contribute to the development of a devastating form of dementia known as Alzheimer's disease. The results of the study provided scientists with evidence that vitamin D affects the transport of proteins, which helps to naturally clear the brain of protein buildup.
Vitamin D can dramatically change the course of development and progression of many diseases, including cancer, heart disease and diabetes. vegan recipes at likelida.com Scientists now believe that Alzheimer's could be included in this list. Getting vitamin D through exposure to sunlight or by taking prohormone supplements should be considered a must for all people wanting.
Vitamin D Helps Cleanse Deadly Amyloid Protein Plaques From The Brain
During the experiment, scientists used data on the health status of laboratory mice, genetically predisposed to the development of dementia. At the same time, the animals were injected with vitamin D. It was found that this vitamin selectively prevents the accumulation of beta-amyloid, and special transporting proteins cleanse cells of destructive amyloids before they can accumulate. The brain possesses a number of special transporting proteins known as LRP-1 and P-GP that accompany amyloid proteins across the blood-brain barrier before they can do any harm.
The researchers believe that vitamin D improves the movement of amyloid-beta across the blood-brain barrier by regulating protein expression through receptors. However, vitamin D also regulates the transmission of cell impulses through the MEK metabolic pathway. The results of these experiments showed scientists new ways to solve the problems associated with the treatment and prevention of Alzheimer's disease.
Controlling Vitamin D Blood Levels Reduces Risk of Alzheimer's Dementia
The researchers believe that vitamin D helps transport the amyloid-beta structures of proteins across the sensitive blood-brain barrier, facilitating the separation of clusters in the cerebrospinal fluid for subsequent elimination. This ability is known to deteriorate with age, allowing sticky protein clusters to accumulate around neuronal synapses. Scientists have found that older people diagnosed with Alzheimer's disease tend to have low levels of vitamin D. At the moment, researchers have established a link between the level of saturation of the blood with this vitamin and the development of disease.
The authors of the study do not say what the optimal level of vitamin D should be. However, many previous experiments have shown that the best blood level of this substance, for possible, is 50-80 ng / ml. Most health conscious people need to take an oil-based vitamin D supplement in order to fully protect themselves against this deadly form of dementia.
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Unexpected results from Scripps Research Institute and ModGene, LLC could completely change scientists' understanding of Alzheimer's disease - one of the most common human neurodegenerative diseases - pointing to the liver instead of the brain as a source of amyloid peptides that are deposited in the form of brain plaques with this devastating disease. This discovery offers a relatively simple approach to the treatment and prevention of Alzheimer's disease.
The researchers used a mouse model of Alzheimer's disease to identify genes that influence the amount of amyloid protein accumulating in the brain. They identified three genes that protect against amyloid deposition and accumulation in animal brains. The mouse brains were protected by a decrease in the expression of each of these genes in liver cells. One of them encodes presenilin, a cellular membrane protein thought to contribute to the development of Alzheimer's disease.
"This unexpected discovery opens the door to the development of new treatments for Alzheimer's disease," said research leader Gregor Sutcliffe, research leader. "It can greatly facilitate the development of methods for its treatment and prevention."
An estimated 5.1 million Americans suffer from this neurodegenerative disease, including nearly half of those 85 and older. If science does not find a way to prevent its development and effective treatments, by 2050 the number of patients aged 65 and over will range from 11 to 16 million. In addition to human suffering, this is an enormous economic burden. A new report from the Alzheimer's Association of the United States (Alzheimer's Association) shows that in the absence of methods of positive impact on disease, the total cost of caring for patients with Alzheimer's between 2010 and 2050 will be $ 20 trillion.
In search of a solution to the riddle of Alzheimer's disease, Sutcliffe and his collaborators have focused over the past several years on naturally occurring differences in susceptibility to neurological disease in different strains of mice, creating an extensive database of gene activity in different tissues. These data provide trait expression maps that can be superimposed on disease modifier gene maps.
As with almost all scientific discoveries, Sutcliffe's research builds on earlier evidence. Several years ago, scientists at Case Western Reserve mapped three genes that modify the accumulation of abnormal amyloid-beta in the brains of transgenic mice with a model of Alzheimer's disease, in large sections of chromosomes, each containing hundreds of genes. Using crosses of B6 and D2 mice, they studied more than 500 of their offspring.
Based on the results of this study, Sutcliffe applied his gene expression databases to a mouse model of Alzheimer's disease, looking for differences in gene expression that correlated with differences in disease susceptibility in the B6 and D2 lines. This intensive work included the creation of computer programs that identified each genetic difference between the B6 and D2 genomes, and the mathematical analysis of their correlation (known as regression analysis). Correlations were made between genotypic differences (B6 and D2) and the amount of messenger RNA produced from more than 25,000 genes in a particular tissue in 40 recombinant inbred mouse strains. These correlations were calculated for 10 tissue types, one of which was the liver.
“One of the key aspects of this work was learning how to ask questions of massive databases to collect information about the identity of inherited modifier genes,” says Sutcliffe. “It was a new and, in a sense, innovative work: we invented a new way of identifying modifier genes, combining all these steps and automating the process. We realized that we could find out how the pathogenic transgenic effect is modified without studying the transgenic mice themselves. ”
The gene hunt has identified good candidates for each of the three modifier genes discovered by Case Western scientists, and one of these candidates - a mouse gene corresponding to a human gene, one variation of which predisposes to early onset of Alzheimer's disease - was of particular interest to scientists. ...
“The product of this gene, the protein presenilin 2, is part of an enzyme complex involved in the formation of the pathogenic amyloid beta,” explains Sutcliffe. “Surprisingly, the inherited expression of presenilin 2 was found in the liver, not the brain. More active expression of presenilin 2 in the liver correlated with a greater accumulation of beta-amyloid in the brain and the development of pathology corresponding to Alzheimer's disease. "
This discovery suggested that significant concentrations of beta-amyloid may originate in the liver, circulate in the blood, and enter the brain. If this is true, blocking the production of amyloid-beta in the liver could protect the brain.
To test this hypothesis, Sutcliffe and his colleagues set up an in vivo experiment using wild-type mice, since they most accurately reproduce the environment in which the natural synthesis of beta-amyloid occurs. "We decided that if brain amyloid is born in the liver and transported to the brain by blood, then it can be observed in all mice," says Sutcliffe, "and predictably in humans."
The mice were injected with imatinib (trade name Gleevec, an FDA-approved cancer drug), a relatively new drug currently approved for the treatment of chronic myeloid leukemia and gastrointestinal tumors. The drug dramatically reduces the synthesis of beta-amyloid in neuroblastoma cells transfected with amyloid precursor protein (APP), as well as in cell-free extracts obtained from transfected cells. It is important to note that Glivec poorly penetrates the blood-brain barrier in both mice and humans.
“It was this property of the drug that determined our choice,” explains Sutcliffe. "Since it does not cross the blood-brain barrier, we were able to focus on the synthesis of amyloid outside the brain and how this synthesis can promote amyloid accumulation in the brain, where it is associated with disease."
Mice were injected with Glivec twice daily for seven days. Plasma and brain tissue were then collected and the amount of beta-amyloid in the blood and brain was measured. Result: the drug dramatically reduced the amount of beta-amyloid not only in the blood, but also in the brain, where it could not penetrate. Thus, a significant part of the brain amyloid had to be synthesized outside the brain, and imatinib is a candidate for the role of a drug for the prevention and treatment of Alzheimer's disease.
With regard to the future of this study, Sutcliffe hopes to find partners and investors to conduct clinical trials and develop new drugs.
If the skin surface becomes rough, darkish bumps appear on it, this may indicate metabolic disturbances, which leads to the accumulation of a pathological protein - amyloid in these places. Do not postpone a visit to the doctor: you can wait for the protein to replace the skin tissue over time, and it will cease to perform its functions. Without proper therapy, structural changes will affect the internal organs.
When only skin tissue is damaged, lichenoid skin amyloidosis is diagnosed. It is treatable, monitored by a dermatologist and, perhaps, it will be necessary to use local remedies constantly. If the disease is systemic, then the amyloid is deposited in the internal organs, a therapist and other specialists are involved in therapy. Next, we'll talk about how to distinguish these conditions and what can be done when symptoms appear.
What is amyloidosis and why you should be afraid of it
Amyloidosis is a chronic disease, which is a violation of protein metabolism, resulting in the formation of amyloid in the body. Its peculiarity lies in the fact that it disrupts the interaction of tissue enzymes, and, being formed around the vessels, squeezes them, which leads to the death of a part of the organ. Amyloidosis can be figuratively compared to a fire: here and there, "hot spots" are formed, they destroy everything in their path, gradually merging with each other. The organ in which the amyloid protein is deposited is gradually affected - if the process is not stopped - its structure is completely replaced by the pathological protein.
Classification
Official classification of amyloidosis:
- The primary systemic process, when amyloid is deposited in both the skin and internal organs. This is due to the fact that by inheritance (familial amyloidosis) or by chance a certain combination of genes appears that are responsible for the formation of modified cells in internal organs or skin, which synthesize the amyloid precursor protein.
- Secondary systemic amyloidosis. Skin and internal organs are involved in the pathological process. The causes of secondary amyloidosis are diseases that provide the body with toxins for a long time. These are tuberculosis, leprosy, chronic bronchitis, syphilis, bronchiectasis, nephritis, rheumatoid arthritis, ulcerative colitis, long-standing caries, tonsillitis.
- Deposition of amyloid locally in the skin - lichenoid (lichen-like) amyloidosis. It is also divided into 2 types. The first is a primary process that occurs for unknown reasons (idiopathic amyloidosis) or due to changes in genes. The second type is secondary cutaneous amyloidosis. It develops against the background of various (usually chronic) dermatological diseases: seborrheic wart, various types, neoplastic skin diseases,.
Most often, amyloid is deposited in the skin during the primary lichenoid process, followed by primary systemic amyloidosis. If the formation of amyloid occurs systemically, against the background of chronic diseases, the skin is rarely affected (more often the heart and kidneys are affected).
Symptoms
The clinical picture with various forms of skin amyloidosis is somewhat different.
Primary systemic process
The skin is not immediately affected. At first, there are symptoms of damage to some internal organ. Usually the heart suffers first; this is manifested in the development of cardiac arrhythmias, pain in it. With the deposition of amyloid in the walls of the stomach and intestines, constipation, nausea, sometimes reaching vomiting develop. The defeat of the muscles is expressed in their soreness and is reflected in the movements in the joints: their amplitude decreases.
The patient's face becomes pale, the tongue sometimes increases in size to such an extent that it may not fit in the mouth. Then there are skin symptoms: hard nodules, plaques, or small swellings; their color is paler than the rest of the covers. Rarely, primary cutaneous amyloidosis is manifested by a blistering rash: then elements filled with bloody contents are located in places of constant friction with clothing.
The rash is localized, mainly in the places of natural skin folds: in the armpits, in the groin and thighs; may appear around the eyes and even in the mouth. Merging with each other, the elements form rough areas, the color of which is darker than in other areas. The rash elements do not differ in itching or pain.
Secondary system process
Before the skin manifestations of the disease, a person coughs for a long time (if the reason is tuberculosis, chronic bronchitis or bronchiectasis), freezes more, especially in the lumbar region (if the reason is kidney damage), his bones or joints hurt. Against this background of general ill health, various elements of the rash appear. Some of them are dense and disc-shaped, with a dark pink color. Others are yellowish, dense nodules. Still others resemble plaques when they do not peel off. It is impossible not to notice them: the foci intensely itch.
Elements of a rash are localized on the chest, neck, face, mouth, which does not close well due to the fact that the tongue becomes large and swollen.
Secondary cutaneous amyloidosis
It develops against the background of a long-term current dermatological disease (most often it is neurodermatitis or). At the same time, the primary elements change, a rough rash similar to "goosebumps" appears in them.
If Vidal's lichen occurs with secondary skin amyloidosis, then the disease develops as follows:
- Initially, severe itching appears on an unchanged area of the skin. This usually occurs in the folds of the joints, on the back of the neck, on the vulva, or between the buttocks. The itching worsens in the evening and at night, and is almost not felt in the morning.
- The lesion changes color from red to brown, elements of a towering rash of various shapes appear. If you feel this place, you feel dry and hard skin, in small "goose bumps".
- Further, the affected area becomes denser and dry. Its color changes to pink-coffee; it is crossed by long furrows running at different angles.
- By the time dark, raised nodules appear, the affected area may have almost disappeared, leaving a patch of darker (less often lighter) skin.
Primary lichenoid amyloidosis
Symptoms occur on previously clean skin. These are nodules, spots or plaques with the following characteristics:
- Are tapered or flat (wart-like)
- dense consistency;
- multiple elements of the rash that do not merge with each other;
- brown color;
- localization: legs, thighs, sometimes - the face;
- the rash is located symmetrically;
- severe itching is felt in the affected areas;
- areas of too white, depigmented skin may appear between the rash elements.
Establishing diagnosis
Diagnosis of skin amyloidosis is rather difficult, as the disease is similar to many other dermatological diseases. It is carried out by a dermatologist. He can only make a diagnosis on the basis of a histological examination, taking a biopsy of the affected area.
To find out if a system or local process is taking place, you need to run a series of instrumental tests. So, it is necessary to conduct ultrasound examinations (ultrasound): of the heart, gastrointestinal tract, spleen, kidneys, muscles. If, according to the results of an ultrasound scan, the doctor is alarmed by the size of an organ, to clarify its defeat, it is necessary to undergo magnetic resonance imaging. The fact that it is amyloid that has been deposited in the internal organ can be found out only after a biopsy.
Therapy
Treatment of pathology is extremely conservative and very long-term. To do this, apply:
- treatment of the elements of the rash with ointments with glucocorticoids: "Prednisolone", "Cloveit", "Kutiveit";
- applications with Dimexide diluted 1:10 with water, some doctors add colchicine;
- with severe itching on the elements of the rash, you can apply "Dikain", "Lidocaine" or another anesthetic;
- laser therapy;
- oral administration of cyclophosphamide, antimalarial drugs;
- taking vitamins B and PP, A and E;
- intradermal administration of glucocorticoids: "Prednisolone", "Hydrocortisone";
- intramuscular injection of a 5% unitiol solution.
Forecast
The pathology can be completely cured only with a local, lichenoid form. Constant observation by a dermatologist is required to monitor for possible relapse. With systemic forms, it is only possible to stop the formation of amyloid protein, but it is impossible to remove it from the internal organs.
After age 65, the risk of developing Alzheimer's disease doubles every 5 years. Now, a new study has found that the brain's ability to excrete toxic protein fragments associated with disease is significantly reduced in older adults.
After age 65, the risk of developing Alzheimer's disease doubles every 5 years.
In the Annals of Neurology, researchers at the University of Washington in St. Louis, Missouri, described how they found that the brains of older people take much longer to clear amyloid beta 42, the main ingredient in protein plaques that accumulate in the brain when Alzheimer's disease.
Randall J. Bateman, senior author and professor of neuroscience, said: “We found that people in their 30s usually take about 4 hours to clear half of amyloid-beta 42 from the brain. In this new study, we have shown that at the age of 80, this process takes more than 10 hours. "
If not cleared, there is a better chance that amyloid-beta 42 - a protein fragment that is a natural byproduct of brain activity - will clot into plaques that disrupt brain functions such as communication between cells.
Scientists have long suspected that these plaques are a major contributor to Alzheimer's, a form of dementia (dementia).
Dementia is a progressive disease in which memory, thinking and behavior deteriorate until the patient can no longer maintain conversation and look after himself. Although this disease mainly affects the elderly, it is not a normal part of aging.
According to the World Health Organization, approximately 48 million people worldwide suffer from dementia, and this figure is growing by almost 8 million every year. Alzheimer's disease accounts for about two-thirds of these cases.
Lower Excretion Values for Amyloid-Beta 42 in People with Symptoms of Alzheimer's Disease
In their study, Professor Bateman and his colleagues tested 100 volunteers between the ages of 60 and 87. Half of these participants showed clinical signs of Alzheimer's disease, such as memory problems, and 62 participants had plaque formation in the brain.
The researchers determined the presence of these signs and symptoms during detailed mental and physical examinations that the participants underwent. In addition to scanning the brain to check for plaque, the researchers tested the participants' cerebrospinal fluid using technology they developed themselves.
Using this technology - called SILK (stable isotope-linked kinetics) - the researchers were able to observe what happens to amyloid-beta 42 and other proteins.
In participants who saw evidence of plaque, the researchers found that amyloid-beta 42 was more prone to leak out of the brain fluid and accumulate in the plaque.
In addition, lower rates of excretion of amyloid-beta 42 - such as those that researchers saw in older participants - were associated with symptoms of Alzheimer's disease, including memory impairment, personality changes, and dementia.
Professor Bateman says scientists believe the brain has four ways of utilizing amyloid-beta: moving it to the spinal cord, moving across the blood-brain barrier, dissolving or absorbing with other proteins, and plaque deposition. He concludes:
“With additional research such as this, we hope to determine which of the first three ways to utilize beta-amyloid slows down as the brain ages. This can help us try to develop new treatments. ”
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