Amyloid plaques in brain tissue testing. Why we don't all get Alzheimer's: a new hypothesis about the trigger of the disease

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 too many protein molecules in the wrong spatial conformation appear in the nerve cells of the brain, which, due to their irregularity, stick together and form insoluble complexes that harm the neuron and, eventually leading him to death. Not every protein is pathogenic; in the case of Alzheimer's disease, it is amyloid beta and tau protein, and one of characteristic features diseases - 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 such 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 mouse brain. (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, and, on the other hand, destroy already formed deposits, that is, those very notorious plaques. Many 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 were given in best case only a very moderate effect. But with antibodies produced by employees of the biotech company Biogen, Inc. , things are quite 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 drug of such antibodies was called adjucanumab (aducanumab). Experiments with transgenic mice in which deposits of human amyloid formed in the brain showed that antibodies injected into the blood penetrate the brains of animals, bind to filamentous amyloid accumulations, converting them into a soluble state, and activate microglial cells, which represent the brain region. immune system. (Normal immune cells that roam our bodies can't get into the brain.) Activated microglia begin to literally absorb the amyloids that have been made soluble by adjucanumab.

But these are animals, besides transgenic, but what about people? To participate in clinical trials, 165 patients aged 50 to 90 years were invited, 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 it is not yet clinically manifested. Some of the participants in the experiment received a placebo, while others four groups used the preparation of antibodies in different concentrations. Immunoglobulins were administered 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 amyloid deposits and thereby made them visible to the tomograph.

In general, as the authors of the work write in Nature, Alzheimer's plaques in humans were noticeably reduced, and this reduction was even called "unprecedented" - compared with other attempts of this kind. The disappearance of amyloid deposits was the more active, the higher the dose of the experimental drug. Some cognitive tests have shown that those patients who received the antibody preparation did not decline in mental ability as quickly as those who received the placebo, and that again everything depended on the dose of the drug. At the same time, it is worth noting that other tests did not find any cognitive differences. On the other hand, some experts, in particular Ronald Petersen ( Ronald Petersen) from the Mayo Clinic, say that while it is not necessary to attach great importance to assessments of cognitive state - in order for them to become reliable, more subjects and more time for research are needed.

Now comes the next stage clinical trials in which more people participate. The researchers hope that they will be able not only to confirm the initial results, but also to understand how to deal with a side effect that was especially noticeable in some patients who received highest dose of the drug - tomography showed that they had small edema and microscopic hemorrhages in some parts of the brain, leading to headaches. One explanation is that amyloid deposits sometimes form close to the blood vessels, and when these deposits begin to pull apart the antibodies, the vessels react to their work somewhat painfully. But, we repeat, we would like to hope that in further clinical experiments side effects will be able to overcome.

Kidney damage may indicate:

• Proteinuria ( the appearance of protein in the urine). Is the first and most significant manifestation kidney damage in amyloidosis. Normally, the concentration of protein in the urine does not exceed 0.033 g / l, however, if the integrity of the renal filter is violated, blood cells and large molecular proteins begin to be excreted in the urine. Proteinuria more than 3 g / l indicates a pronounced nephrotic syndrome and severe defeat kidney tissue.
• Hematuria ( the appearance of red blood cells in the urine). Normally, with a microscopic examination of urine, no more than 1-3 erythrocytes are allowed per field of view. Blood in the urine may indicate the development of nephrotic syndrome or be a sign of an inflammatory lesion of the renal tissue ( glomerulonephritis).
• Leukocyturia ( the appearance of leukocytes in the urine). Microscopic examination of urine allows the presence of 3-5 leukocytes in the field of view. Leukocyturia is rarely observed in renal amyloidosis and more often indicates the presence of an infectious and inflammatory disease of the kidneys or other organs of the genitourinary system.
• Cylindruria ( the presence of casts in the urine). Cylinders are casts that form in the renal tubules and have a different structure. In amyloidosis, they are usually formed from desquamated renal epithelial cells and proteins ( hyaline casts), but may also contain erythrocytes and leukocytes.
• Decreased density of urine. The normal density of urine ranges from 1.010 to 1.022, however, with the destruction of the renal nephrons, the concentration ability of the organ decreases markedly, as a result of which the density of urine will decrease.

Blood chemistry

This study allows not only to assess the functional state of internal organs, but also to suspect the cause of amyloidosis.

Diagnostic value in amyloidosis are:

• proteins of the general phase of inflammation;
• cholesterol level;
• the level of proteins in the blood;
• creatinine and urea levels.

Proteins of the general phase of inflammation
These proteins are produced by the liver and some white blood cells in response to the development of an inflammatory process in the body. Their main function is to maintain inflammation, as well as prevent damage to healthy tissues.

Acute phase proteins

Protein	Normal values
Serum protein amyloid A(SAA)	Less than 0.4 mg/l.
Alpha 2 globulin	M: 1.5 - 3.5 g / l.
	F: 1.75 - 4.2 g / l.
Alpha 1 antitrypsin	0.9 - 2 g / l.
C-reactive protein	Not more than 5 mg/l.
fibrinogen	2 - 4 g / l.
lactoferrin	150 - 250 ng / ml.
ceruloplasmin	0.15 - 0.6 g / l.

It should be noted that a progressive increase in the concentration of fibrinogen in the blood is also often found in hereditary forms of amyloidosis, which must be taken into account when assessing this indicator.

Liver tests
This group includes a number of indicators to assess the functional state of the liver.

Liver tests for liver amyloidosis

Indicator	What does	Norm	Changes in liver amyloidosis
Alanine aminotransferase(AlAT)	These substances are contained in the liver cells and enter the bloodstream in large quantities only with massive destruction of the tissue of the organ.	M: up to 41 U / l.	The concentration increases with the development of liver failure.
		F: up to 31 U / l.
Aspartate aminotransferase(ASAT)
Bilirubin total	When RBCs break down in the spleen, unbound bilirubin is formed. With the blood flow, it enters the liver, where it binds to glucuronic acid and, in this form, is excreted from the body as part of bile.	8.5 - 20.5 µmol/l.	The concentration increases with massive deposition of amyloid in the liver.
Bilirubin (unrelated faction)		4.5 - 17.1 µmol / l.	The concentration increases with liver failure and violation of the bile-forming function of the organ.
Bilirubin (related faction)		0.86 - 5.1 µmol / l.	The concentration increases with compression of the intrahepatic or extrahepatic bile ducts.

Blood cholesterol level
Cholesterol is a fatty substance that is formed in the liver and plays an important role in maintaining the integrity of the membranes of all body cells. An increase in the concentration of cholesterol in the blood of more than 5.2 mmol / l can be observed with nephrotic syndrome, and the higher this indicator, the more severe the disease.

The level of proteins in the blood
Norm total protein in the blood is 65 - 85 g / l. A decrease in this indicator can be observed with the development of nephrotic syndrome ( due to loss of protein in the urine), as well as in severe liver failure, since all body proteins are synthesized in the liver.

Creatinine and urea levels
Urea ( norm - 2.5 - 8.3 mmol / l) is a by-product of protein metabolism that is excreted through the kidneys. Creatinine ( the norm is 44 - 80 µmol / l in women and 74 - 110 µmol / l in men) is formed in muscle tissue, after which it enters the bloodstream and is also excreted by the kidneys. An increase in the concentration of these substances in the blood is a very sensitive indicator of the degree of impaired renal function in amyloidosis.

Ultrasound examination of internal organs

This study allows you to evaluate the structure and structure of internal organs, which is necessary to assess the degree of violation of their function and determine the prevalence pathological process.

Ultrasound in amyloidosis can reveal:

• Compaction and increase ( or decrease in the azotemic stage) kidneys.
• Presence of renal cysts what could cause secondary amyloidosis).
• Enlargement and thickening of the liver and spleen, as well as impaired blood flow in these organs.
• Hypertrophy of various parts of the heart muscle.
• Amyloid deposits in the walls of large vessels ( For example, the aorta is the largest artery in the body.).
• Accumulation of fluid in body cavities ascites, hydrothorax, hydropericardium).

genetic research

Genetic testing is ordered if hereditary amyloidosis is suspected ( that is, if it is not possible to confirm the secondary nature this disease ). Usually, a polymerase chain reaction is used for this, the principle of which is to take genetic material from a sick person ( usually blood, urine, saliva, or any other bodily fluid) and the study of genes on certain chromosomes. The detection of genetic mutations in a certain area will be one hundred percent confirmation of the diagnosis.

If one of the forms of hereditary amyloidosis is detected, a genetic study is recommended for all family members and close relatives of the patient in order to exclude the presence of this disease in them.

Biopsy

A biopsy is a lifetime taking a small piece of tissue or an organ and examining it in the laboratory using special techniques. This study is the "gold standard" in the diagnosis of amyloidosis and allows you to confirm the diagnosis in more than 90% of cases.

With amyloidosis for research can be taken muscle, tissue of the liver, spleen, kidney, intestinal mucosa or other organ ( depending on the clinical picture of the disease). The sampling is carried out in a sterile operating room, usually under local anesthesia. With the help of a special needle with sharp edges, the skin is punctured and a small amount of organ tissue is taken.

In the laboratory, part of the obtained material is treated with Lugol's solution ( iodine in aqueous solution potassium iodide), followed by 10% sulfuric acid solution. In the presence of a large amount of amyloid, it will turn blue-violet or greenish, which will be visible to the naked eye.

For microscopic examination, the material is stained with special dyes ( for example, Congo red, after which amyloid acquires a specific red color), and examined under a microscope, with amyloid fibrils clearly defined as randomly located rod-shaped formations.

Amyloidosis treatment

It is rather difficult to identify amyloidosis and start treatment at the early stages of its development, since the disease manifests itself clinically decades after its onset. At the same time, when expressed kidney failure therapeutic measures are ineffective and are supportive.

Is hospitalization required to treat amyloidosis?

If amyloidosis is suspected, hospitalization in the department of nephrology or therapy is recommended in order to conduct a thorough examination of the genitourinary system, since kidney damage is the most frequent and at the same time the most dangerous complication of amyloidosis. Specialists from other fields of medicine should also be involved ( hepatologist, cardiologist, neurologist and so on) to identify and treat damage to other organs and systems.

If during the diagnostic process no serious functional disorders were detected on the part of any organs, further treatment can be carried out on an outpatient basis ( at home) provided that the patient will strictly comply with all doctor's prescriptions and come to the control at least once a month.

The main indications for hospitalization are:

• the presence of a systemic inflammatory process ( laboratory or clinically confirmed);
• the presence of a purulent infectious disease;
• nephrotic syndrome;
• kidney failure;
• liver failure;
• heart failure;
• adrenal insufficiency;
• severe anemia ( hemoglobin concentration less than 90 g/l);
• hypersplenism;
• internal bleeding.

If the patient's condition worsens during outpatient treatment, he should also be hospitalized to clarify the diagnosis and correct treatment.

In the treatment of amyloidosis is used:

• drug treatment;
• diet therapy;
• peritoneal dialysis;
• organ transplant.

Medical treatment

Drug treatment is aimed at slowing down the process of amyloid formation ( if possible). good efficiency observed in the case of AL-amyloidosis, while in other forms of the disease it is not always possible to achieve a positive result. Secondary amyloidosis responds worst to medical treatment.

Medical treatment of amyloidosis

Drug group	Representatives	Mechanism therapeutic effect	Dosage and administration
Steroid anti-inflammatory drugs	Prednisolone	Inhibit immune reactions, have a pronounced anti-inflammatory effect. They reduce the rate of formation of lymphocytes, and also inhibit the migration of leukocytes to the focus of inflammation, which is the reason for the positive effect in amyloidosis.	Dosage, duration of use and route of administration is selected individually in each case, depending on the severity of the underlying and concomitant diseases.
	Dexamethasone
Anticancer drugs	Melphalan	Disrupts the process of DNA formation ( deoxyribonucleic acid), which inhibits protein synthesis and cell reproduction. Since amyloidoblasts are considered to be mutant to a certain extent ( tumor) cells, their destruction can slow down the formation of amyloid ( especially in the primary form of the disease).	Inside, once a day at a dose of 0.12 - 0.15 mg / kg. The duration of treatment is 2-3 weeks, after which it is necessary to take a break ( at least 1 month). If necessary, the course of treatment can be repeated.
Aminoquinoline drugs	Chloroquine (hingamin)	An antimalarial drug that also inhibits DNA synthesis in cells human body, reducing the rate of formation of leukocytes and amyloidoblasts.	Inside, 500 - 750 mg daily or every other day. The duration of treatment is determined by the effectiveness and tolerability of the drug.
Anti-gout drugs	Colchicine	It inhibits the rate of formation of leukocytes and the process of synthesis of amyloid fibrils in amyloidoblasts. Effective in familial Mediterranean fever and to a lesser extent in secondary amyloidosis.	Inside, 1 mg 2-3 times a day. Long term treatment ( over 5 years).

diet therapy

There is no specific diet that could prevent the development of amyloidosis or slow down the process of amyloid formation. The main complications of amyloidosis requiring compliance strict diet are nephrotic syndrome and renal failure. With the development of these syndromes, diet number 7 is recommended, the purpose of which is to protect the kidneys from the action of toxic metabolic products, normalize the water-salt balance and blood pressure.

It is recommended to eat food in small portions 5-6 times a day. The main condition is to limit the consumption of table salt ( no more than 2 grams per day) and liquids ( no more than 2 liters per day), which to a certain extent prevents the formation of edema and normalizes blood pressure. The difficulty in this case lies in the need to replenish protein losses in nephrotic syndrome and at the same time reduce their intake with food, since renal failure disrupts the process of excretion of by-products of their metabolism.

Diet for amyloidosis

What is recommended to use?	What is not recommended?
vegetable broths; lean meats ( beef, veal) no more than 50 - 100 grams per day; salt-free bread and pastries; fresh fruits ( apples, plums, pears, etc.); fresh vegetables ( tomatoes, cucumbers, potatoes, etc.); rice ( no more than 300 - 400 grams per day); 1 - 2 egg whites per day ( without salt); milk and dairy products; weak tea; freshly squeezed juices.	meat and fish products in large quantities; sweet pastries; some fruits ( apricots, grapes, cherries and currants); dried fruits; cheese products; egg yolk; coffee; mineral and carbonated drinks; alcohol.

Peritoneal dialysis

The principle of this method is similar to the principle of hemodialysis ( which is described earlier), but there are some differences. In peritoneal dialysis, the semipermeable membrane through which metabolic by-products are removed is the peritoneum, a thin, well-perfused serous membrane that lines the inner surface and organs. abdominal cavity. total area The peritoneum is close to the surface area of ​​the human body. A special solution is introduced into the abdominal cavity through a catheter ( tube in the stomach) and comes into contact with the peritoneum, as a result of which metabolic products begin to seep into it from the blood, that is, the body is cleansed. The "disadvantage" of this method is a slower blood purification than with hemodialysis.

The main advantages of this method over hemodialysis are:

• Excretion of B 2 -microglobulin, which can cause the development of amyloidosis.
• Constant ( continuous) purification of the blood from metabolic by-products.
• Can be used on an outpatient basis at home).

Execution technique
The catheter is inserted in the operating room under local or general anesthesia. Usually it is installed in the lower part of the abdominal wall, and only a small segment of it comes out. About 2 liters of a special dialysis solution is injected through the catheter into the abdominal cavity, after which the catheter is tightly closed and the fluid remains in the abdominal cavity for a period of 4 to 10 hours. During this time, the patient can engage in almost any daily activity.

After a set period of time ( usually every 6 to 8 hours) it is necessary to drain the "old" solution from the abdominal cavity and replace it with a new one. The whole procedure takes no more than 30-40 minutes and requires minimal effort.

Peritoneal dialysis is contraindicated:

• in the presence of adhesions in the abdominal cavity;
• with infectious diseases of the skin in the abdomen;
• with mental illness.

Organ transplant

Donor organ transplantation is the only way to save the lives of patients with developed organ failure. However, it is worth remembering that this method treatment is only symptomatic and does not eliminate the cause of the development of amyloidosis, therefore, in the absence of constant adequate treatment, a relapse of the disease is possible.

With amyloidosis, it is possible to transplant:

• kidney;
• liver tissue;
• a heart;
• skin.

Donor organs can be obtained from a living donor ( except for the heart), as well as from a corpse or from a person diagnosed with brain death, however, the functional activity of internal organs is maintained artificially. In addition, today there is artificial heart, which is a fully mechanized apparatus that can pump blood in the body.

If the donor organ takes root ( which doesn't always happen), the patient requires lifelong use of immunosuppressants ( drugs that suppress the activity of the immune system) to prevent rejection of the "foreign" tissue by the body's own.

Complications of amyloidosis

The consequences of amyloidosis usually include various acute conditions developing against the background of impaired functions of one or more organs. Often these complications lead to the death of the patient.

The most dangerous complications of amyloidosis are:

• Myocardial infarction. With an increase in systemic blood pressure ( always observed in nephrotic syndrome and renal failure) the load on the heart muscle increases several times. This condition is aggravated by the deposition of amyloid in the tissue of the heart, which further impairs its blood supply. As a result, during sudden physical exertion or emotional stress, a discrepancy between the need of the heart muscle for oxygen and the level of its delivery may develop, which can lead to the death of cardiomyocytes ( muscle cells of the heart). If a person does not die immediately ( which is seen quite often), a scar is formed in the infarction zone, which further “weakens” the heart ( since scar tissue is not able to contract) and can lead to congestive heart failure.
• Stroke. A stroke is an acute interruption of the blood supply to the brain tissue. In amyloidosis, the condition usually develops as a result of bleeding through a deformed wall of a blood vessel ( hemorrhagic stroke). As a result of impregnation nerve cells they die with blood, which, depending on the stroke zone, can manifest itself in the most different symptoms from sensory disturbances and motor activity until the death of the patient.
• Thrombosis of the hepatic veins. This complication may develop as a result of an increase in the concentration of fibrinogen ( blood coagulation protein) in the renal vein system, which leads to the formation of blood clots, which clog the lumen of the vessels. As a result, acute renal failure develops. The mechanism of development of this complication is due to the fact that in nephrotic syndrome a large amount of albumin is released through the kidneys ( major plasma proteins), while fibrinogen remains in the blood and its relative concentration increases.
• Infectious diseases. The depletion of defense systems, the loss of a large amount of proteins in the urine and the development of multiple organ failure makes the patient's body practically defenseless against various pathogenic microorganisms. Amyloidosis is often associated with pneumonia ( pneumonia), pyelonephritis and glomerulonephritis, skin infections ( erysipelas ) and soft tissues, food poisoning, viral infections ( e.g. parotitis) etc.

Is pregnancy possible with amyloidosis?

Pregnancy with amyloidosis is possible only in cases where functional activity is vital important organs women are enough to carry and give birth to a child. Otherwise, the pregnancy may end in the death of both the fetus and the mother.

Some local forms of amyloidosis do not pose any danger to pregnancy. If the accumulation of amyloid occurs in only one organ or tissue ( for example, in a muscle or in the intestinal wall) and does not reach large sizes, pregnancy and childbirth will proceed without complications, and the child will be born absolutely healthy. At the same time, in generalized forms of amyloidosis, the prognosis for the mother and fetus is entirely determined by the duration of the disease and the remaining functional reserves of vital organs.

The outcome of pregnancy and childbirth is determined by:

• heart functions;
• kidney function;
• liver functions;
• functions of the adrenal glands;
• rate of amyloid formation.

Functions of the heart
A dangerous complication of amyloidosis is heart failure ( CH), which develops due to the deposition of amyloid in the tissue of the heart. This leads to a violation of its contractile activity, as a result of which certain symptoms appear during exercise - weakness, shortness of breath ( feeling short of breath), heart palpitations, chest pain. Since the bearing of a child and childbirth are accompanied by a significant load on the heart, damage to this organ can cause serious complications during pregnancy.

Depending on the severity, 4 functional classes of heart failure are distinguished. The first is characterized by the appearance of symptoms only in extremely severe physical activity, while the fourth is for patients who are unable to care for themselves. Women with functional class I - II can safely bear a child, but artificial delivery is recommended for them ( by caesarean section). In the presence of III - IV functional class, pregnancy and childbirth are absolutely contraindicated, since the body in this case will not be able to cope with the increasing load. The probability of death of the fetus and mother in this case is extremely high, therefore, artificial termination of pregnancy is recommended ( abortion by medical indications ).

Kidney Functions
The developing fetus needs a constant supply of various nutrients, including proteins. However, with the deposition of amyloid in the kidneys of the mother, the destruction of the renal tissue occurs, as a result of which blood cells and large molecular proteins begin to be excreted in the urine, which ultimately leads to severe protein deficiency, edema and ascites ( accumulation of fluid in the abdominal cavity). The fetus also begins to lack protein ( which are the main building material for a growing organism), as a result of which there may be a delay in development, and after birth, malformations, stunting, mental and psychic abnormalities may be noted.

The extreme degree of kidney damage in amyloidosis is chronic renal failure, in which the kidneys are unable to remove metabolic by-products from the body. As a result, they accumulate in the mother's blood, exerting a toxic effect on all organs and systems, which can also affect the condition of the fetus ( from mild developmental delay to fetal death).

Liver functions
When amyloid is deposited in the liver tissue, the blood vessels of the organ are compressed, resulting in increased pressure in the system of the so-called portal vein, which collects blood from all unpaired organs of the abdominal cavity ( from the stomach, intestines, spleen and other). The veins of these organs expand, and their walls become thinner. With a further increase in pressure, the liquid part of the plasma begins to leave the vascular bed and accumulate in the abdominal cavity, that is, ascites develops. If it accumulates enough, it begins to put pressure on the growing fetus. This can result in developmental delay, various congenital anomalies, and with severe intense ascites ( if the amount of liquid exceeds 5 - 6 liters) intrauterine fetal death may occur.

Adrenal functions
IN normal conditions The adrenal glands secrete certain hormones involved in the regulation metabolic processes in organism. When affected by amyloidosis, the amount of functional tissue in these organs decreases, resulting in a marked decrease in hormone production.

During pregnancy, the adrenal hormone cortisol plays an important role, the function of which is to activate adaptive mechanisms in the mother's body. With its deficiency, these mechanisms are extremely weak or completely absent, as a result of which any physical or emotional trauma can lead to the death of the fetus and mother.

Rate of amyloid formation
Usually, this process proceeds rather slowly, due to which at least ten years pass from the onset of the disease to the development of multiple organ failure. However, in some cases ( usually with secondary amyloidosis, which develops against the background of chronic purulent-inflammatory processes in the body) amyloid is formed very quickly. This can result in amyloid infiltration of placental vessels ( organ responsible for metabolism between mother and fetus), which will lead to oxygen starvation fetus, developmental delay, or even intrauterine death.

Does amyloidosis occur in children?

Children suffer from amyloidosis somewhat less frequently, which is obviously related to the time required for the development of the pathological process ( it usually takes several years). However, in some forms of hereditary amyloidosis, as well as in secondary amyloidosis, it is possible to damage the internal organs in the early childhood.

The cause of amyloidosis in children can be:

• Familial Mediterranean fever. A genetically determined disease that is inherited in an autosomal recessive manner, that is, a child will be born sick only if he inherits the defective genes from both parents. If a child receives a defective gene from one parent, and a normal one from the second, he will be an asymptomatic carrier of the disease, and his children can inherit defective genes with a certain degree of probability. Clinically, this disease is manifested by generalized amyloidosis, which develops in the first 10 years of life. The renal tissue is predominantly affected. In addition to amyloidosis, there are bouts of fever ( fever, chills, increased sweating) And mental disorders.
• English amyloidosis. It is characterized by a predominant lesion of the kidneys, as well as bouts of fever and hearing loss.
• Portuguese amyloidosis. The clinical picture is dominated by nerve damage. lower extremities, which is manifested by a feeling of crawling, a violation of sensitivity and movement disorders. The prognosis for life is favorable, but paralysis often develops ( inability to perform voluntary movements).
• American amyloidosis. It is characterized by a predominant lesion of the nerves upper limbs. Clinical manifestations are the same as in Portuguese amyloidosis.
• secondary amyloidosis. This form of the disease develops in the presence of chronic purulent-inflammatory processes in the body ( tuberculosis, osteomyelitis, syphilis and others). If the baby was infected during childbirth or immediately after birth, it is likely that after 5 to 10 ( and sometimes less) years, he will begin to show the first signs of generalized amyloidosis. The prognosis in this case is extremely unfavorable - multiple organ failure develops quite quickly and death occurs. The ongoing treatment gives positive results only in half of the cases and for a short period of time, after which the disease usually recurs ( escalates again).

Is there an effective prevention of amyloidosis?

Effectiveness of primary prevention ( aimed at preventing the development of the disease) depends on the form of amyloidosis and the timeliness of preventive measures. Secondary prevention ( aimed at preventing recurrence of the disease) is ineffective and does not give the desired results.

Prevention of amyloidosis

Form of amyloidosis	a brief description of	Preventive actions
Primary(idiopathic amyloidosis)	The cause of this form of the disease is unknown.	None.
hereditary amyloidosis	The development of amyloidosis in this case is associated with the presence of mutant genes on certain chromosomes ( in the human genetic apparatus there are only 23 pairs of them). These genes are passed down from generation to generation, as a result of which all the offspring of a sick person can develop amyloidosis with a certain degree of probability. Defective genes trigger the formation of mutant cells ( amyloidoblasts), synthesizing fibrillar proteins, which are subsequently converted into amyloid and deposited in body tissues.	Since the disease occurs even at the conception of a child ( at the fusion of 23 maternal and 23 paternal chromosomes), postnatal prophylaxis ( carried out after the birth of a child) is inefficient. The only effective measure is the genetic study of the fetus in the early stages of intrauterine development ( up to 22 weeks of pregnancy). When identifying the genes responsible for the development of amyloidosis, it is recommended to terminate the pregnancy for medical reasons. If any of the closest relatives of a person had amyloidosis, he and his wife ( spouse) it is also recommended to undergo a genetic examination in order to identify a latent form of the disease ( carriage).
Secondary amyloidosis	The development of this form of the disease occurs in chronic inflammatory process in the body - with glomerulonephritis ( inflammation of the kidney tissue), tuberculosis, osteomyelitis ( purulent process in bone tissue) and others. In this case, the concentration of a special protein in the blood increases - the serum amyloid precursor, which causes the development of the disease.	Prevention consists in timely and full treatment chronic inflammatory and purulent processes in the body. This is done by using antibacterial drugs broad spectrum ( penicillins, ceftriaxone, streptomycin, isoniazid and others) until the disappearance of clinical and laboratory manifestations of the disease, as well as for a certain period of time after a complete cure.

How long do people with amyloidosis live?

In the presence of a detailed clinical picture of amyloidosis ( with symptoms of multiple organ failure) the prognosis is generally poor - more than half of patients die within the first year after diagnosis. However, more often it is possible to diagnose the disease at an earlier time. In this case, the prognosis for life is determined by the form of amyloidosis, as well as the severity of damage to vital organs. In any form, the disease is more severe in older people.

Survival of patients with amyloidosis is affected by:

• Kidney function. With the development of renal failure, the patient dies within a few months. Hemodialysis ( blood purification with a special device) prolongs the life of the patient by 5 years or more. A kidney transplant can be effective method treatment, however, deposition of amyloid in the donor organ is observed in more than half of the cases.
• Liver function. With severe portal hypertension ( increased pressure in the portal vein) there is an expansion of the veins of the internal organs ( intestines, esophagus, stomach). A patient with such symptoms can die at any time as a result of bleeding from a ruptured vein. The life expectancy of such patients without radical treatment ( liver transplants) does not exceed 1–2 years.
• Function of the heart. With the development of grade VI heart failure, most patients die within 6 months. Heart transplantation can prolong the life of patients ( provided that other organs and systems function normally).
• bowel function. In intestinal amyloidosis, malabsorption can reach an extreme degree of severity. In the absence specific treatment (complete intravenous nutrition) the death of the patient can occur within a few weeks due to the extreme degree of exhaustion of the body ( cachexia).

Depending on the form of the disease, there are:

• Idiopathic generalized amyloidosis. The cause of the disease is unknown. It is manifested by the defeat of all organs and tissues, the rapid development of multiple organ failure and the death of the patient. A year after the diagnosis, only 51 people out of a hundred remain alive. The five-year survival rate is 16%, while the ten-year survival rate is no more than 5%.
• hereditary amyloidosis. If the disease develops in early childhood, the prognosis is poor. Death usually occurs due to kidney failure within a few years of diagnosis.
• secondary amyloidosis. Forecast is determined functional state internal organs. The main cause of death in this form of the disease is also chronic renal failure.

Local ( local) forms of amyloidosis usually represent tumor-like formations of various sizes ( from 1 - 2 to tens of centimeters in diameter). In the process of growth, they can compress neighboring organs, but timely surgery allows you to eliminate the disease. There is practically no threat to life.

Can amyloidosis be cured with folk remedies?

There are folk methods that have been used for many years in the treatment of this disease. However, it should be noted that self-treatment with such serious illness how amyloidosis can lead to the most undesirable consequences so before using folk recipes it is highly recommended to consult a doctor.

For amyloidosis, you can use:

• Herbal anti-inflammatory infusion. The composition includes fresh flowers of field chamomile ( have anti-inflammatory and antimicrobial action ), immortelle flowers ( have an anti-inflammatory effect, and also improve the excretion of bilirubin in bile), St. John's wort ( increases physical and mental endurance) and birch buds ( have a diuretic effect). To prepare the infusion, place 200 grams of each ingredient in a glass jar and pour a liter of boiling water. After that, tightly close the lid and leave in a dark place for 5-6 hours. Take 200 ml once a day at bedtime. The duration of continuous treatment is not more than 3 months.
• Infusion from the fruits of mountain ash and blueberries. To prepare the infusion, you need to take 100 grams of the fruit of each berry and pour a liter of boiling water. After half an hour, strain, let cool and take 100 ml 3 times a day before meals. The infusion has an anti-inflammatory and astringent effect.
• Infusion from deaf nettle. This plant contains tannins, ascorbic acid, histamine and many other substances. Used for chronic infectious diseases kidneys. To prepare the infusion, 3-4 tablespoons of chopped nettle herb should be poured into a thermos with 500 milliliters hot water (not boiling water) and take 100 milliliters 4 to 5 times a day.
• Infusion of juniper fruit. It has anti-inflammatory, antimicrobial, choleretic and diuretic effects. To prepare the infusion, 1 tablespoon of dried berries must be poured with 1 liter of boiling water and infused in a dark place for 2 to 4 hours. Take 1 tablespoon 3-4 times daily before meals.
• Tincture of grass of sowing oats. It has anti-inflammatory and general tonic effect. Increases the efficiency and stress resistance of the body. To prepare the tincture, pour 200 mg of crushed oat herb with 70% alcohol and infuse in a dark place for 3 weeks, shaking the jar daily. After that, strain and take 1 teaspoon 3 times a day, diluted in 100 ml of warm boiled water.

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 process of transporting proteins, which helps to naturally clear the brain of their accumulation.

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 To date, scientists believe that Alzheimer's disease can be included in this list. Getting Vitamin D by Being Under sunbeams or when taking supplements with prohormones should be considered a must for all people who wish.

Vitamin D helps clear the brain of deadly amyloid protein plaques

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 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 do any harm.

Researchers believe that vitamin D improves the movement of beta-amyloid across the blood-brain barrier by regulating protein expression via 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 blood levels of vitamin D reduces the risk of Alzheimer's dementia

Researchers believe that vitamin D helps transport beta-amyloid protein structures across the sensitive blood-brain barrier, helping to break down 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. Researchers have found that older people diagnosed with Alzheimer's tend to have low level vitamin D. At the moment, researchers have established a relationship between the level of saturation of the blood with this vitamin and the development of diseases.

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

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The proteins involved in the development of Alzheimer's disease are found in the brain of every person, but despite this, the vast majority of people do not get sick and will never get sick. Alzheimer's disease. What is the basis of such "inequality"?

β-secretase(BACE) is involved in the breakdown
amyloid precursor protein(APP)
with education amyloid beta(β-amyloid),
which aggregates, forming characteristic
Alzheimer's disease extracellular
senile plaques (β-amyloid plaque).
(Fig. withfriendship.com)

Why don't we all get Alzheimer's? For the cell biologist Subojita Roy(Subhojit Roy), MD, PhD, this question is of particular interest as Dr. Roy is Associate Professor in the Department of Pathology and Neurology at the University of California, San Diego School of Medicine.

In an article published in the journal Neuron, Dr. Roy and his colleagues explain this phenomenon: in their opinion, the wisdom of nature lies in the fact that most people retain the vital physical separation of the protein and the enzyme that breaks it down, the interaction of which is the trigger for the progressive degeneration and death of cells characteristic of the disease Alzheimer's.

"It's like physically separating gunpowder and matches to forestall the inevitable explosion," says Dr. Roy. “Knowing exactly how these gunpowder and matches are separated, we can develop new ideas about how to stop the disease.”

The severity of Alzheimer's disease is measured by the loss of functional neurons. There are two "tell" signs of this disease: protein clots amyloid beta- so called beta amyloid plaques, - accumulating outside neurons, and aggregates of another protein called tau, forming neurofibrillary tangles inside nerve cells. Most neuroscientists believe that the cause of Alzheimer's disease is the formation and accumulation of beta-amyloid plaques, causing a cascade of molecular events leading to cell dysfunction and cell death. Thus, this so-called "The Amyloid Cascade Hypothesis" puts beta-amyloid at the center of the pathology of Alzheimer's disease.

An interaction is necessary for the formation of beta-amyloid amyloid precursor protein(APP) and enzyme beta secretases(BACE), which breaks down APP into smaller toxic fragments.

Top: vesicles containing APP(green)
And BACE(red) usually physically
separated. Bottom: after neuronal stimulation,
increasing synthesis amyloid beta, bubbles
with APP and BACE converge (shown in yellow),
and the proteins begin to interact.
(Photo: UC San Diego School of Medicine)

“Both of these proteins are expressed in the brain on high level, explains Dr. Roy, “and if we let them interact continuously, we will all have Alzheimer's disease.”

However, this does not happen. Experimenting with cultured hippocampal neurons and human and mouse brain tissues, Dr. Roy and his colleagues found that in healthy brain cells, BACE-1 and APP tend to be separated and in different compartments from the very moment they are formed, which excludes their contact.

"Nature seems to have come up with an interesting trick to separate these accomplices," says Dr. Roy.

In addition, it turned out that conditions that enhance the synthesis of beta-amyloid protein also enhance the interaction of APP and BACE-1. In particular, an increase in the electrical activity of neurons, which, as is known, stimulates the synthesis of beta-amyloid, also leads to an increase in the interaction between APP and BACE-1. The study of autopsy brain samples from Alzheimer's patients showed an increase in the physical proximity of these proteins, confirming the pathophysiological significance of this phenomenon.

The results of the study are critical because they shed light on some of the earliest molecular trigger events in Alzheimer's disease and show how healthy brains are protected from them. From a clinical point of view, they outline new possible directions in the treatment or even prevention of disease.

To a certain extent, this is an unconventional approach. But, according to the first author of the article, Dr. Utpala Dasa(Utpal Das), "The most interesting thing is that we might be able to screen for molecules that can physically separate APP and BACE-1."

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Scientists at the University of Michigan have discovered a new useful property epigallocatechin gallate (EGCG) - a bioactive substance found in green tea leaves. The results of their study prove that EGCG prevents the misfolding of certain brain proteins, including those associated with development. Alzheimer's disease. (Photo: University of Michigan)

Scientists at the University of Michigan University of Michigan, U-M) have discovered a useful new property of one of the molecules found in green tea: it prevents the misfolding of specific brain proteins. The aggregation of these proteins, called metal-associated amyloid beta, connected with Alzheimer's disease and others neurodegenerative diseases .

U-M Mi Hee Lim, Associate Professor of Chemistry, Life Sciences Institute, PhD, and an interdisciplinary team of scientists studied the effect of green tea extract on aggregate formation metal-associated beta-amyloids in vitro. The results of their experiments are presented in a paper recently published in the journal Proceedings of the National Academy of Sciences .

Scientists have found that in vitro a compound found in green tea epigallocatechin-3-gallate(epigallocatechin-3-gallate, EGCG) interacts more actively with metal-associated beta-amyloids (containing, in particular, copper, iron and zinc) than with metal-free peptides, forming small unstructured aggregates. In addition, when live cells were incubated with EGCG, the toxicity of both metal-free and metal-bound beta-amyloids was reduced.

Associate Professor of Chemistry, Life Sciences Institute U-M Mi Hee Lim, PhD. (Photo: lsi.umich.edu)

To gain insight into the structure of the interactions and understand this reactivity at the molecular level, the scientists used ion mobility mass spectrometry (IM-MS), 2D NMR spectroscopy, and computational methods. Experiments have shown that EGCG interacts with beta-amyloid monomers and dimers to form more compact peptide conformations than when bound to untreated EGCG beta-amyloids. In addition, ternary EGCG–metal–Aβ complexes were formed.

Dr. Lim's research team consisted of chemists, biochemists, and biophysicists.

“There is a lot of interest in this molecule,” says Dr. Lim, noting that EGCG and other compounds found in natural products Flavonoids have long been considered powerful antioxidants. "We used A complex approach. This is the first example of an interdisciplinary study focusing on a framework by three scientists from three different fields of science.”

According to Lim, although small molecules and metal-associated beta-amyloids studied by many scientists, most of the researchers consider them from their own, narrow point of view.

Neuroscientist Bing Ye. (Photo: umms.med.umich.edu)

"But because the brain is very complex, we think a combination of several approaches is needed."

Article in PNAS is the starting point, the scientist continues, and the next step in the research will be to test the ability of a slightly modified EGCG molecule to prevent plaque formation in fruit flies.

"We want to modify the molecule in such a way that it specifically interferes with the formation of plaques associated with Alzheimer's disease," explains Lim.

She plans to continue her work in collaboration with LSI neuroscientist Bing Ye. Together, the researchers will test the new molecule's ability to suppress the potential toxicity of protein and metal-containing aggregates in fruit flies.

Based on materials

Original article:

S.-J. Hyung, A. S. DeToma, J. R. Brander, S. Lee, S. Vivekanandan, A. Kochi, J.-S. Choi, A. Ramamoorthy, B. T. Ruotolo, M. H. Lim. Insights into antiamyloidogenic properties of the green tea extract (-)-epigallocatechin-3-gallate towards metal-associated amyloid-β species

© "Green tea extract prevents the formation of beta-amyloid plaques in Alzheimer's disease." Full or partial reprinting of the material is allowed with a mandatory active hyperlink to the page that is not closed from indexing, not prohibited for the robot to follow Alzheimer's disease. Written permission is required.

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