Drug antibodies inhibit Alzheimer's disease. How can cholesterol plaques be dissolved in blood vessels? Beta amyloid plaques

The results of a study by scientists from the Northwestern University Feinberg School of Medicine, USA, showed that beta-amyloid, a pathological protein, the accumulation of which is the main sign of the development of Alzheimer's disease, begins to be deposited inside human neurons from the age of 20 . The results of the study were published in the journal Brain.

According to lead researcher Changiz Geula, research fellow from the Center for Cognitive Neurology and Alzheimer's Disease Center at Northwestern University Feinberg, unprecedented data were obtained that amyloid begins to accumulate in the human brain from a young age. According to Geula, this has great importance, since it is known that if amyloid for a long time found in the human body, it negatively affects his health.

American scientists studied cholinergic neurons in the basal forebrain, trying to explain the cause of their early damage and why these cells are among the first to die during natural aging and Alzheimer's disease. These sensory neurons necessary for maintaining memory and attention.

Geula and his colleagues examined neurons obtained from the brains of three different groups patients - 13 cognitively healthy people aged 20-66 years, 16 elderly aged 70-99 years without dementia, 21 patients with Alzheimer's disease aged 60-95 years.

The results of the study showed that amyloid molecules begin to be deposited inside these neurons at a young age, and this process continues throughout a person's life. Similar amyloid deposition was not observed in nerve cells in other areas of the brain. In the cells studied, amyloid molecules formed tiny toxic plaques, amyloid oligomers, which can be detected even in young people as young as 20 years old. The size of amyloid plaques increased in older people and patients with Alzheimer's disease.

According to Geul, the findings provide insight into the early death of basal forebrain neurons, which may be due to small amyloid plaques. In his opinion, the accumulation of amyloid in these neurons during human life, likely makes these cells susceptible to pathological processes during aging and to the loss of neurons in Alzheimer's disease.

With a high degree of probability, growing plaques can damage and even cause the death of neurons - they can provoke an excessive flow of calcium into the cell, which can lead to its death. The plaques can become so large that the cell's degradation machinery can't dissolve them and they clog up the neuron, Geul says.

Additionally, plaques can cause damage by secreting amyloid outside the cell, leading to the formation of large amyloid plaques found in Alzheimer's disease.

Original article:
Alaina Baker-Nigh, Shahrooz Vahedi, Elena Goetz Davis, Sandra Weintraub, Eileen H. Bigio, William L. Klein, Changiz Geula. Neuronal amyloid-β accumulation within cholinergic basal forebrain in aging and Alzheimer’s disease. Brain, March 2015 DOI:

Only the lazy have not heard about “bad” cholesterol. Everyone knows that it can be deposited on the walls of blood vessels and lead to various diseases that cholesterol can cause a stroke or heart attack. Therefore, upon reaching conscious adulthood, many people wonder how to cleanse blood vessels from atherosclerotic plaques in order to avoid these consequences. Let's talk about this from the point of view of not traditional, but official medicine.

What are cholesterol plaques

Each human organ receives nutrition from vessels, of which there is a huge and extensive network in the body. Blood flowing through the vessels is not a solution, but a suspension, when a suspension of cells, called formed elements, floats in the liquid. The liquid part of the blood does not at all resemble water, which is explained by the molecules dissolved in it, mainly of a protein nature. But they also “float” in the blood various products fat metabolism, in particular cholesterol, triglycerides, lipoproteins.

According to the laws of physics, blood moves through the vessels in such a way that a “trickle” flows in the center, practically free of cells, and most of the formed elements “go” along the edges, representing a kind of “quick response department”: in response to damage to the blood vessels, they immediately descend from here platelets, “closing” the gap.

The liquid part of the blood also comes into contact with vascular walls. As we remember, the products of fat metabolism are dissolved in it. There are several different ones, cholesterol is only one of the components. This system is structured as follows: normally, “bad” fats are in balance with their antagonists, “good” fats (“good” cholesterol). When this balance is disturbed - either the number of “bad” ones increases, or the volume of “good” ones decreases - on the walls arterial vessels fatty tubercles - plaques - begin to be deposited. The risk of depositing such plaques is judged by the ratio of good fats (they are called “high-density lipoproteins” - HDL) and the sum of low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL). This can be done using a blood test from a vein, called a lipid profile.

Such a plaque is dangerous in the following ways:

• It can come off and, having passed with the blood flow to a vessel of “suitable” diameter, clogs it, thereby depriving the area feeding from there of some kind of nutritional organ. The smaller the vessel, the smaller the area that dies, the less the functioning of this organ and the body as a whole is disrupted (there is “duplication” within the tissue of each organ, thanks to which each “piece” receives nutrition from several small-diameter vessels at once).
• The blood is forced to bypass the plaque, as a result of which, instead of a uniform flow in the vessel, “vortices” are created when part of the blood flowing near the wall covered with the plaque has to return back. Turbulence in the blood flow impairs the nutrition of the blood supply to the organ. Here the relationship is the same as in the point above: the larger the diameter of the artery damaged by the plaque, the more the organ suffers.
• If the composition of the blood does not change, and the amount of HDL and enzymes that should “break off” the plaque does not increase, the body tries to limit it. To do this, he sends immune cells to the site of plaque deposition, whose task is to “bite off” pieces of the plaque and digest them. But the cells are unable to do this: instead of digesting, the immune cells are damaged by cholesterol and fats, and remain “lying” around the cholesterol. Then the body decides to cover this formation with connective tissue, and the plaque increases in size even more, now worsening the blood supply to the organ not only due to turbulence, but due to a decrease in the lumen of the vessel.
• Covering with connective tissue is good for the plaque and bad for the vessel. Now, if something damages the plaque, it will “call” platelets to itself, which will form a blood clot on its surface. This phenomenon, firstly, will further reduce the diameter of the vessel, and secondly, it will increase the risk (especially in vessels with “active” blood flow) of a blood clot breaking off and blocking a smaller vessel.
• A long-existing plaque becomes covered with calcium salts. Such a wall formation is already stable and will not come off without intervention. But it tends to grow and reduce the lumen of the vessel.

The rate of plaque formation is affected by:

• consumption of animal fats;
• smoking;
• diabetes;
• excess weight;
• physical inactivity;
• high blood pressure;
• binge eating;
• eating large amounts of simple carbohydrates with food.

The localization of plaque deposition is unpredictable: it can be either the arteries supplying the brain or the arteries of the kidneys, limbs or other organs. Depending on this, they can cause:

• ischemic stroke;
• angina pectoris;
• myocardial infarction;
• intestinal gangrene;
• aortic aneurysm;
• discirculatory encephalopathy, which is manifested by memory deterioration, headaches, decreased ability to analyze what is happening;
• deterioration of blood supply to a larger or smaller area of ​​the limb, up to its gangrene;
• if the plaque blocks the aorta in the area where large vessels originate from it to each of the lower extremities, both legs will suffer only from ischemia or gangrene.

How to determine if there are cholesterol plaques

Before cleaning blood vessels from cholesterol plaques and blood clots, you need to find out whether they are there or not. If the lipid profile shows the risk of plaque formation, the coagulogram shows the risk of thrombus formation, then instrumental studies will help to detect immediate “congestion” in the vessels:

• A special type of ultrasound is color duplex scanning . In this way it is very convenient to examine arterial and venous vessels upper and lower extremities, aorta, vessels going to the brain and those that nourish the retina;
• Triplex scanning is another ultrasound option. It is used to examine the vessels of the brain and the arteries that supply it - those located outside the cranial cavity;
• The most accurate research method is angiography. It is used to clarify the location of plaques/thrombi in the vessels of the extremities that were identified during duplex or triplex scanning, as well as to determine blood clots/plaques in those organs that cannot be seen during ultrasound examination.

When to clean vessels

You need to clear cholesterol from your blood vessels when:

• according to instrumental methods atherosclerotic plaques or
• when there is already a violation internal organs, against which a high atherogenic index was detected (according to lipid profile). This:
  • cholesterol above 6.19 mmol/l;
  • LDL – more than 4.12 mmol/l;
  • HDL: below 1.04 for men, below 1.29 mmol/l for women.

In the following cases, it is necessary to do everything possible to prevent the deposition of cholesterol on the walls of blood vessels:

• men over 40 years old;
• women over 55 years old;
• if you have bad habits;
• if a person eats a lot of smoked, fried, salty food, meat;
• if relatives have atherosclerosis, ischemic or hypertension;
• suffering from diabetes mellitus;
• those who note the presence of excess weight;
• those who have suffered a complication of streptococcal infections such as rheumatism;
• if at least once there was numbness of one limb or half of the body, which did not follow their compression, but arose “on its own”;
• if at least once there was a visual impairment in one eye, which then went away;
• when there was an attack of sudden general weakness;
• if there is causeless pain in the navel area, accompanied by flatulence and constipation;
• when memory deteriorates, and the desire to rest causes less and less mental stress;
• if it becomes more and more difficult to walk, your legs hurt with less and less load;
• when there is chest or cardiac pain that is not relieved by nitroglycerin;
• if the hair on your legs falls out, and your legs themselves turn pale and freeze;
• if any ulcers, redness, or swelling begin to appear on the lower extremities.

What you need to do before you start cleaning blood vessels from plaques

In order not to encounter the fact that cleaning blood vessels at home will result in blood clots or plaques being pulled away from the walls with corresponding consequences, before carrying out it you need to be examined:

1. take a coagulogram so that the laboratory can determine not only standard indicators, but also the INR index;
2. take a lipid profile;
3. be sure to perform an electrocardiogram.

How to clean blood vessels from atherosclerotic plaques

The program for cleaning blood vessels from cholesterol deposits on their walls should be left by the doctor based on the results of laboratory and instrumental studies. It must include:

1. lifestyle changes if they lead to the formation of plaques;
2. adherence to a diet that will lead to the normalization of the functioning of the digestive organs, so that “good” cholesterol is best absorbed;
3. a diet that will prevent blood clots.

According to indications, the following may be prescribed:

1. medications that reduce blood cholesterol levels;
2. drugs that reduce blood viscosity;
3. folk remedies aimed at normalizing blood viscosity or reducing cholesterol levels.

Step 1. Do not let “bad” cholesterol increase

Without this action, all further measures - whether folk recipes, drugs - will not have the desired effect, since the person will continue to saturate the body with cholesterol.

This can only be done with diet:

• when dishes are prepared by baking or boiling;
• there is a sufficient amount of cereals;
• with lots of vegetables and fruits;
• with products containing polyunsaturated omega-3 fatty acids;
• when there is enough seafood;
• dairy products are low-fat.

You need to exclude:

Step 2. Diet to stop blood clots

To prevent the formation of blood clots on atherosclerotic plaques, which are dangerous because they can break off at any time, follow the following diet (it is almost identical to the one that limits the intake of cholesterol:

Step 3. Lifestyle changes

Without such measures, the following steps are ineffective. Otherwise, blood will stagnate in the vessels, which is very popular with blood clots and atherosclerotic plaques. As measures to “clean” blood vessels, you need to:

• sleep enough time, as dictated by the endocrine and nervous systems. When the organs that make them up come into balance, they will also try to ensure a normal balance between the coagulation and anticoagulation, atherosclerotic and anti-atherosclerotic systems;
• move more, eliminating blood stagnation;
• spend more time in the fresh air, ensuring a sufficient flow of oxygen;
• prevent the formation of excess weight;
• control blood glucose levels, whose increased level damages blood vessels;
• prevent long-term existence of arterial hypertension, which also deforms the vascular wall;
• follow the principles of the diet described above.

Step 4. Drugs to cleanse blood vessels from blood clots

To prevent blood clots, tablets are used to prevent the deposition of platelets on the walls of blood vessels. These are “Thrombo-Ass”, “CardioMagnil”, “Plavix”, “Clopidogrel”, “Aspecard”, “Curantil” and others.

If the INR is low according to the coagulogram, anticoagulant drugs are prescribed and there are atherosclerotic plaques or blood clots; not only the aspirin-based antiplatelet agents mentioned above are prescribed, but also drugs that affect the blood coagulation system. This injectable drugs"Clexan", "Fragmin", "Fraxiparin", in the worst case - injectable "Heparin". You can also use the drug "Warfarin". The dosage is selected by the doctor. After starting to take such drugs, be sure to monitor the INR by adjusting the dose of the drug, otherwise bleeding may begin.

Step 5. Hirudotherapy

Treatment with medicinal leech bites prevents the formation of blood clots in blood vessels. This occurs due to the fact that this worm, when sucking, releases various enzymes into the blood. They should serve to ensure that while the leech drinks blood, it does not clot. As a result, hirudin and other enzymes enter the systemic circulation, dissolving existing small blood clots and preventing further thrombus formation.

Hirudotherapy cannot be performed by everyone, but only in the absence of:

• blood clotting disorders;
• exhaustion;
• pregnancy;
• caesarean section or other surgery performed within 4 months ago;
• hypersensitivity to one of the components of leech “saliva”;
• persistent low blood pressure.

Before you cleanse blood vessels with folk remedies, consult your cardiologist or therapist to see if you can take this or that decoction.

• rowan;
• white willow bark;
• tansy;
• nettle;
• strawberry leaves;

For the same purpose, you can purchase certified dietary supplements from herbal pharmacies: hawthorn and rosehip syrup, “Beets with celery,” “Hawthorn Premium.” If you don’t like the taste of garlic, buy the dietary supplement “Garlic Powder” from Solgar. Ginkgo biloba, produced in the form of dietary supplements, thins the blood very well.

Common folk recipes

Here are the 2 most common recipes.

• You need garlic and lemon. You need to take them by weight in equal quantities and grind them in a meat grinder. Now add the same amount of honey as this mixture, stir. Leave for a week in a sealed container, stirring occasionally. Drink the mixture once a day, 4 teaspoons.
• Take 5 tbsp. pine needles, 3 tbsp. rose hips, 1 tbsp. onion peel. Pour this mixture into 1 liter cold water, then bring the infusion to a boil and simmer for 10 minutes. Then turn off the heat, cover the pan and leave overnight. In the morning, strain the mixture and drink it in small portions throughout the day.

A possible step is drugs to dissolve cholesterol plaques

In some cases, with a high atherogenic index (determined by a blood test for lipids), it is advisable to prescribe drugs that will dissolve atherosclerotic plaques. Only a cardiologist or therapist can make such a prescription, since only he is able to assess the balance between the risk of side effects and the potential benefits of these drugs.

There are 2 main types of cholesterol-lowering drugs prescribed. These are statins (Atorvacard, Simvastatin, Lovastatin and others) and fibrates (Clofibrate, Tycolor, Esklip).

Statins

Statins are drugs that lower cholesterol by blocking the enzyme pathway by which it is synthesized. Although these medications are included in the plan compulsory treatment atherosclerosis, prescribed by the Ministry of Health, but due to the large number of side effects, the doctor will think whether it is worth prescribing them, or whether treatment can be carried out without their use. They are mandatory for use by the following categories of persons:

• during acute period myocardial infarction;
• those who have had a heart attack or stroke;
• before and after heart surgery;
• pronounced ischemic disease heart when the level of myocardial infarction is high.

With a low risk of developing a heart attack, if there is diabetes mellitus, as well as in women before menopause, the use of such drugs can cause side effects from any of the body systems. If you try to treat only high cholesterol levels with statins, when a person’s heart, kidneys and liver are healthy, it is quite risky, especially since the harmful effects here develop gradually, gradually. But if you have already decided to cleanse the vessels in this way, you need to monitor your blood biochemical parameters monthly, especially what is called “liver tests.” It is also not worth reducing or increasing the dosage on your own.

Fibrates

These are drugs that reduce the production of cholesterol: Clofibrate, Gemfibrozil, Tycolor and others. They are not as good at lowering cholesterol as statins, but they are not as toxic either. These 2 groups of drugs are most often combined to reduce the number of side effects.

Other groups of drugs

In some cases, medications that are aimed at reducing cholesterol intake are effective. These are Orlistat, Xenical, Ezetrol. Their effectiveness is not as high as that of statins or fibrates, since most of the “bad” lipoproteins are still produced by the body’s own, and are not absorbed from food.

In the absence of indications for taking statins, but in the presence of diabetes mellitus, hypertension, chronic cholecystitis or cholelithiasis, such bad habit like smoking, dietary supplements can be used. Such products, which come in capsules or tablets and are not considered “real” drugs, are sometimes just as effective in clearing plaque from blood vessels without causing huge amount unpleasant side symptoms. These are “Tykveol”, “Lipoic acid”, “Omega Forte”, “Doppelgerts omega 3”, “CardioActive Hawthorn”, “Golden mumiyo”.

Possible step - surgery

When an atherosclerotic plaque is “overgrown” with calcium salts so that no drug reaches its cholesterol core or folk remedy. At the same time, it does not provide nutrition to any organ or threatens the development of a stroke or gangrene. In this case, the only solution is surgery to remove plaque from the vessels. At the same time, a “bypass” is created for the blood supply to the suffering organ, for example, coronary artery bypass surgery, when an additional “path” is created from the overlying area to the vessel that goes directly to the tissue in need. Thus, the blood flows past the “clogged” area of ​​the vessel. Sometimes a stenting operation is performed, when a “tube” (stent) is placed in the area of ​​the narrowed artery, returning the vessel to its original lumen diameter.

After such interventions, long-term use of drugs that reduce blood clots together with drugs that will maintain normal cholesterol levels is necessary to prevent the re-formation of plaques.

Thus, if you want to protect your blood vessels from possible plaque deposits, you need to adjust your lifestyle, drink a course, after consulting with a therapist, decoctions or infusions prepared according to folk recipe. The same applies to people who do not complain of heart problems and discover that they have high cholesterol levels in their blood. If, while walking, performing physical activity or when getting out of bed, pain or discomfort appears behind the sternum or on the left side of the chest; if you suffer from high blood pressure or have previously been diagnosed with a heart defect, you should consult your doctor about the advisability of taking cholesterol-lowering medications.

Remember: don’t get too carried away with lowering cholesterol. This element is needed for the membranes of each of our cells; with a small amount of it, the risk of developing cancer and diseases increases nervous system, including stroke, as well as a condition in which there is a low level of hemoglobin in the blood - anemia.

July 22, 2016

Transparent brain and 3D atlas of amyloid plaques

Researchers from Rockefeller University (USA) used a newly developed imaging technique that makes brain tissue transparent. This allowed them to see a three-dimensional picture of the location of accumulations of pathological protein, beta-amyloid plaques, in the brains of deceased people with Alzheimer's disease.

The presence and distribution of pathological amyloid-beta protein accumulations in the brain, which is considered a “trigger” for the chain of events leading to neuronal death, was until recently determined by analyzing brain slices. Slice preparation is time-consuming, and subsequent 3D reconstruction is laborious and can be inaccurate. In any case, the resulting insight will be limited because the brain is a complex three-dimensional structure, with many interconnected components, that is difficult to fully reconstruct from slice data. We needed a way to see the big picture.

Spatial brain imaging methods such as positron emission and functional magnetic resonance imaging show the activity of various brain areas, but are not suitable for studying the distribution of beta-amyloid. But a recently developed method called iDISCO (immunolabeling-enabled 3D imaging of solvent cleared organs) came in handy.

Brain tissue is approximately 60% fat. If they are removed, the brain becomes, according to scientists, hard and transparent, almost “like glass.” Using the iDISCO method, the brain is impregnated with a composition that gives fat electric charge, and then exposed to an electric field with the opposite charge. It turns out to be a “magnet” that “pulls” fat from the brain.

The plaques themselves were stained using immunological methods, after which they became visible in volume - in the entire hemisphere of the mouse brain and in small fragments of the human brain. It turned out that in mouse models of Alzheimer's disease, plaques are quite small, uniform in size and shape, and not grouped, unlike in the human brain, where heterogeneity is visible, plaques are larger, and complex three-dimensional amyloid structures are observed.

Clumps of beta-amyloid are purple in color

Scientists hope that by comparing the patient's symptoms and the post-mortem pattern of the distribution of beta-amyloid in his brain, it will be possible to learn to distinguish between the types of Alzheimer's disease, which may be not one, but several conditions, because the number of amyloid plaques does not always correspond to the severity of the disease. Sometimes there are a lot of plaques, but dementia does not occur, and sometimes there seem to be no plaques, but there are symptoms of the disease. Perhaps this is the reason why they fail clinical trials drugs being developed: because they have different effectiveness at different options diseases. There is no way yet to distinguish between these options, and three-dimensional visualization of plaques, their location, and analysis of the structures they form can help to learn this.

September 16, 2014

The brain is able to compensate for the harmful effects of amyloid plaques

On early stages With Alzheimer's disease, a person's brain can reorganize in a special way that delays the onset of symptoms of the disease.

read August 22, 2014

Alzheimer's disease: how close are we to solving the problem?

There are very few days when there is not a single report on Alzheimer's disease research in the medical news feeds. However, at what stage of development is this research direction?

read March 25, 2014

Another antidiabetic drug will help with Alzheimer's disease?

The antidiabetic drug pramlintide reduces beta-amyloid plaques in brain tissue and improves learning and memory in two experimental models of Alzheimer's disease.

read December 26, 2012

Will suppressing the immune response help with Alzheimer's disease?

Inactivation of the immune complex that triggers inflammatory reactions in brain tissue, suppresses the course of Alzheimer's disease.

Older 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 evidence for scientists The fact that vitamin D affects the process of transporting proteins, which helps naturally clear the brain of their accumulation.

Vitamin D can dramatically change the development and progression of many diseases, including cancer, heart disease and diabetes. vegan recipes on likelida.com Today, scientists believe that Alzheimer’s disease can also be included in this list. Getting vitamin D by staying under sun rays or when taking prohormone supplements should be considered mandatory for all people wishing to.

Vitamin D helps clear the brain of deadly amyloid protein plaques

During the experiment, scientists used data on the health of laboratory mice genetically predisposed to developing dementia. At the same time, the animals were given injections of vitamin D. It was found that this vitamin selectively prevents the accumulation of beta-amyloid, and special transport proteins clear cells of destructive amyloids before they can accumulate. The brain has a number of special transport proteins known as LRP-1 and P-GP that escort amyloid proteins across the blood-brain barrier before they can cause any harm.

Researchers believe that vitamin D improves the movement of beta-amyloid across the blood-brain barrier by regulating protein expression through receptors. At the same time, 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 problems related to the treatment and prevention of Alzheimer's disease.

Controlling vitamin D levels in the blood reduces the risk of developing Alzheimer's dementia

Researchers believe that vitamin D helps transport beta-amyloid protein structures across the sensitive blood-brain barrier, helping to separate clusters in the cerebrospinal fluid for subsequent elimination. This ability is known to decline with age, allowing sticky protein clusters to accumulate around neuronal synapses. Scientists have found that older adults diagnosed with Alzheimer's disease tend to have low levels of vitamin D. B this moment Researchers have established a connection between the level of blood saturation with this vitamin and the development of diseases.

The study authors do not say what the optimal level of vitamin D should be. However, the results of many previous experiments have shown that the best blood level of this substance to be possible is 50-80 ng/ml. Most health-conscious people need to take an oil-based vitamin D supplement to fully protect themselves from this fatal form of dementia.

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Amyloidosis (amyloid dystrophy, Latin amyloidosis, Greek amylon starch + eidos species + ōsis) is a group of diseases that are distinguished by a wide variety of clinical manifestations and are characterized by extracellular (in the extracellular matrix) deposition (systemic or local) of insoluble pathological fibrillar proteins (protein- polysaccharide complex - amyloid) in organs and tissues that are formed as a result of complex metabolic changes (protein dystrophies). The main target organs are the heart, kidneys, nervous system [central and peripheral], and liver, however, in systemic forms, almost all tissues can be affected (rare localizations include adrenal amyloidosis). They were called amyloids because, in reaction with iodine, they resembled starch. Amyloid persists in the body for a long time and even after death does not rot for a long time (I.V. Davydovsky, 1967). Amyloidosis can occur independently or “secondarily” as a result of another disease.

Currently, amyloidosis is considered as a group of diseases that are characterized by the deposition in tissues and organs of fibrillar amyloid protein (AFA) - a special protein structure with a diameter of 5 - 10 nm and a length of up to 800 nm, consisting of 2 or more parallel multidirectional (antiparallel) filaments that form cross-β-sheet conformation(see picture on the left). It is this that determines the specific optical property of amyloid - the ability to undergo birefringence (detected by Congo red staining [= method for determining amyloid in tissues]). According to modern data, the prevalence of amyloidosis in the population ranges from 0.1 to 6.6%.

The protein name amyloid was proposed by Rudolf Virchow, who borrowed it from botany, where the word meant cellulose or starch. In its structure, amyloid is a complex glycoprotein in which fibrillar and globular proteins are found in a structure with polysaccharides (galactose, glucose, glucosamine, galactosamines, mannose and fructose). Amyloid contains proteins similar in their characteristics to α1-, β- and γ-globulins, albumin, fibrinogen, and it contains neuraminic acid. The bonds between proteins and polysaccharides are very strong, which maintains its stability. The structure of amyloid also contains a P component, which makes up up to 15% of the total amyloid and is identical to the serum protein SAP (serum amyloid P). SAP is a protein produced by liver cells, classified as acute phase (SAP is a constant component of amyloid deposits in all forms of amyloidosis).

Amyloidosis is polyetiological. Of primary importance is the amyloidogenicity of the major amyloid precursor protein (BPA), which is specific for each form of amyloidosis. Amyloidogenicity is determined by changes in the primary structure of APA, fixed in the genetic code or acquired during life due to mutations. To realize the amyloidogenic potential of BPA, exposure to a number of factors is necessary, such as inflammation, age, and physicochemical conditions in situ.

TABLE: Classification of amyloidosis (in all names of types of amyloidosis, the first letter is uppercase letter"A" stands for the word "amyloid" followed by the designation of the specific AAD - A [amyloid A protein; is formed from the serum precursor protein SAA - an acute phase protein, normally synthesized by hepatocytes, neutrophils and fibroblasts in trace amounts], L [immunoglobulin light chains], TTR [transthyretin], 2M [β2-micro-globulin], B [B protein ], IAPP [islet amyloid polypeptide], etc.).

note! The structural and chemical-physical characteristics of amyloid are determined by the main BPA, the content of which in the fibril reaches 80% and is a specific feature for each type of amyloidosis. Each protein (AP) has significantly different mechanisms of synthesis, utilization, and biological functions, which determines differences in clinical manifestations and approaches to the treatment of amyloidosis. For this reason, different forms of amyloidosis are considered different diseases (see table).

Despite the progress achieved in the study of various types of amyloid, the final stage of amyloidogenesis—the formation of amyloid fibrils in the intercellular matrix of BPA—remains largely unclear. Apparently, this is a multifactorial process that has its own special features when different forms amyloidosis. Let us consider the process of amyloidogenesis using the example of AA amyloidosis. It is believed that in the formation of AA from SAA, the process of incomplete cleavage of SAA by proteases associated with the surface membrane of monocyte-macrophages and the polymerization of soluble AA protein into fibrils, which is believed to also occur with the participation of membrane enzymes, are important. The intensity of AA amyloid formation in tissues depends on the concentration of SAA in the blood. The amount of SAA synthesized by cells of different types (hepatocytes, neutrophils, fibroblasts) increases many times during inflammatory processes and tumors (increased SAA levels in the blood play a major role in the pathogenesis of AA amyloidosis). However, for the development of amyloidosis, only a high concentration of SAA is not enough; the presence of amyloidogenicity in the BPA (i.e., SAA) is also necessary. The development of amyloidosis in humans is associated with SAA1 deposition. Currently, 5 isotypes of SAA1 are known, of which the greatest amyloidogenicity is attributed to isotypes 1.1 and 1.5. The final stage of amyloidogenesis - the formation of amyloid fibrils from BPA - occurs during incomplete cleavage of monocyte-macrophages by proteases. Stabilization of the amyloid fibril and a sharp decrease in the solubility of this macromolecular complex are largely due to interaction with interstitial polysaccharides.

Despite the differences in the types of amyloid protein, there is a common pathogenesis of various clinical forms amyloidosis. The main reason for the development of the disease is the presence of a certain, often increased amount of amyloidogenic APA. The appearance or enhancement of amyloidogenicity may be due to the circulation of protein variants with increased overall hydrophobicity of the molecule, an imbalance in the ratio of surface molecular charges, which leads to instability of the protein molecule and promotes its aggregation into an amyloid fibril. At the last stage of amyloidogenesis, amyloid protein interacts with blood plasma proteins and tissue glycosaminoglycans. Except structural features, the physicochemical properties of the intercellular matrix, where the amyloid fibril is assembled, are also important. Many forms of amyloidosis can also be combined based on their occurrence in old and senile age (AL, ATTR, AIAPP, AApoA1, AFib, ALys, AANF, A-beta), which indicates the presence of mechanisms of age-related evolution of the structure of certain proteins towards increasing amyloidogenicity and allows consider amyloidosis as one of the models of aging of the body.

Neurological aspects of amyloidosis :

ATTR amyloidosis. ATTR amyloidosis includes familial amyloid polyneuropathy, which is inherited in an autosomal dominant manner, and systemic senile amyloidosis. The precursor protein in this form of amyloidosis is transthyretin, a component of the prealbumin molecule, synthesized by the liver and performing the functions of the thyroxine transport protein. It has been established that hereditary ATTR amyloidosis is the result of a mutation in the gene encoding transthyretin, which leads to the replacement of amino acids in the TTR molecule. There are several types of hereditary amyloid neuropathy: Portuguese, Swedish, Japanese and several others. In the most common familial variant (Portuguese), in the 30th position from the N-terminus of the transthyretin molecule, methionine is replaced with valine, which increases the amyloidogenicity of the precursor protein and facilitates its polymerization into amyloid fibrils. Several variant transthyretins are known, which accounts for the variety of clinical forms of hereditary neuropathy. Clinically, this disease is characterized by progressive peripheral and autonomic neuropathy, which is combined with damage to the heart, kidneys and other organs varying degrees. Systemic senile amyloidosis develops after age 70 as a result of age-related conformational changes in normal transthyretin, apparently increasing its amyloidogenicity. The target organs of senile amyloidosis are the heart, cerebral vessels and aorta.

read also the post: Transthyretin amyloid polyneuropathy(to the website)

read also the article “Damage to the peripheral nervous system in systemic amyloidosis” Safiulina E.I., Zinovieva O.E., Rameev V.V., Kozlovskaya-Lysenko L.V.; Federal State Autonomous Educational Institution of Higher Education "First Moscow State medical University them. THEM. Sechenov" Ministry of Health of the Russian Federation, Moscow (magazine "Neurology, neuropsychiatry, psychosomatics" No. 3, 2018) [read]

Alzheimer's disease(AD) is a genetically determined progressive neurodegenerative disease, which is based on the death of neurons in the cerebral hemispheres; clinical manifestations diseases are a decrease in memory and other cognitive functions (intelligence, praxis, gnosis, speech). At the moment, 4 main genes have been identified that are responsible for the development of this disease: gene encoding amyloid precursor protein (APP, chromosome 21), genes encoding enzymes [alpha-, beta-, gamma-secretase] metabolizing APP: presenilin-1 (chromosome 14), presenilin -2 (1st chromosome). A special role is played by hetero- or homozygous carriage of the fourth isoform of apolipoprotein E (APOE 4).

Normally, the amyloid precursor protein (APP) is cleaved by alpha-secretase into soluble (equal in size) polypeptides that are not pathogenic, and (APP) is excreted from the body; in the case of pathology of the genes responsible for the metabolism of APP, the latter is cleaved by beta and gamma secretases into fragments of different lengths. In this case, the formation of insoluble long fragments of amyloid protein (alpha-beta-42) occurs, which are subsequently deposited in the substance (parenchyma) of the brain and the walls of cerebral vessels (stage of diffuse cerebral amyloidosis), which leads to death nerve cells. Next, in the brain parenchyma, aggregation of insoluble fragments occurs into a pathological protein - amyloid beta ("nest" deposits of this protein in the brain parenchyma are called senile plaques). Deposition of amyloid protein in cerebral vessels leads to the development of cerebral amyloid angiopathy, which is one of the causes of chronic cerebral ischemia.

read the article: Cerebral amyloid angiopathy(to the website)

Beta-amyloid and insoluble fractions of diffuse amyloid protein have neurotoxic properties. The experiment showed that against the background of cerebral amyloidosis, tissue inflammatory mediators are activated, the release of stimulating mediators (glutamate, aspartate, etc.) increases, and the formation of free radicals increases. The result of this entire complex cascade of events is damage to neuronal membranes, which is indicated by the formation of neurofibrillary tangles (NFTs) within the cells. NSF are fragments of a biochemically altered inner membrane of a neuron and contain hyperphosphorylated tau protein. Normally, tau protein is one of the main proteins in the inner membrane of neurons. The presence of intracellular NSFs indicates irreversible damage to the cell and its rapid death, after which NSFs exit into the intercellular space (“NPS-ghosts”). The neurons surrounding the senile plaques are the first and most affected.

It takes 10-15 years from the onset of amyloid protein deposition in the brain to the development of the first symptoms of the disease - mild forgetfulness. To a large extent, the rate of progression of asthma is determined by the severity of concomitant somatic pathology, vascular risk factors, as well as the intellectual development of the patient. In patients with high level education and sufficient intellectual load, the disease progresses more slowly than in patients with average or primary education and insufficient intellectual activity. In this regard, the theory of cognitive reserve was developed, according to which, during intellectual activity, the human brain forms new interneuronal synapses and increasingly larger populations of neurons are involved in the cognitive process. This makes it easier to compensate for cognitive defects even with progressive neurodegeneration.

Diagnosis of amyloidosis. Amyloidosis suspected on the basis of clinical and laboratory data must be confirmed morphologically by the detection of amyloid in tissue biopsies. If AL-type amyloidosis is suspected, it is recommended to perform a puncture bone marrow. Most often, to diagnose different types of amyloidosis, a biopsy of the mucous membrane of the rectum, kidney, and liver is performed. A biopsy of the mucous and submucosal layers of the rectum can detect amyloid in 70% of patients, and a kidney biopsy - in almost 100% of cases. In patients with carpal tunnel syndrome, tissue removed during carpal tunnel decompression surgery should be tested for amyloid. To detect amyloid, biopsy material must be stained with Congo red, followed by polarized light microscopy to detect birefringence.

Modern morphological diagnosis of amyloidosis includes not only detection, but also typing of amyloid, since the type of amyloid determines therapeutic tactics. For typing, a test with potassium permanganate is often used. When Congo red-stained preparations are treated with a 5% solution of potassium permanganate, the AA-type amyloid loses its color and loses its birefringence properties, while the AL-type amyloid retains them. The use of alkaline guanidine makes it possible to more accurately differentiate between AA and AL amyloidosis. Most effective method Amyloid typing is performed by immunohistochemical research using antisera to the main types of amyloid protein (specific antibodies against AA protein, immunoglobulin light chains, transthyretin and beta-2-microglobulin).

note! Amyloidosis is a multisystem disease; damage to only one organ is rarely observed. If the history mentions a combination of symptoms such as general weakness, emaciation, easy appearance bruising, early development of dyspnea, peripheral edema, sensory changes (carpal tunnel syndrome) or orthostatic hypotension, amyloidosis should be suspected. Hereditary amyloidosis is characterized by a burdened family history of “neuromuscular” lesions of unknown etiology or dementia, Aβ2M amyloidosis is characterized by the use of hemodialysis, and AA amyloidosis is characterized by the presence of a chronic inflammatory process. Also, amyloidosis must be excluded in patients with kidney diseases of unknown origin, especially with nephrotic syndrome, incl. in patients with restrictive cardiomyopathy. Amyloidosis is more likely in the presence of both of these syndromes. In AA amyloidosis, the dominant target organ, in addition to the kidneys, is the liver, so when differential diagnosis causes of severe hepatomegaly in combination with kidney damage should exclude amyloidosis.

additional literature:

article “Difficulties in diagnosing and treating AL amyloidosis: review of the literature and own observations” by V.V. Ryzhko, A.A. Klodzinsky, E.Yu. Varlamova, O.M. Sorkina, M.S. Sataeva, I.I. Kalinina, M.Zh. Aleksanyan; Hematology Researcher RAMS center, Moscow (magazine “Clinical Oncohematology” No. 1, 2009) [