Preventing the formation of amyloid beta. Amyloidosis of the skin is one of the causes of skin “goosebumps” and “plaques”. Does amyloidosis occur in children?

Proteins involved in the development of Alzheimer's disease are present 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 lies at the heart of this “inequality”?

β-secretase(BACE) is involved in the breakdown
amyloid precursor protein(ARR)
with education beta amyloid(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 disease? For the cell biologist Subojita Roy Subhojit Roy, MD, PhD, this question is of particular interest because Dr. Roy is an associate professor in the departments of pathology and neurology at the University of California, San Diego School of Medicine.

In an article published in the magazine Neuron, Dr. Roy and his colleagues explain this phenomenon: in their opinion, the wisdom of nature is that most people maintain the vital physical separation of protein and its enzyme, the interaction of which is the trigger for the progressive degeneration and cell death characteristic of the disease Alzheimer's.

“This can be compared to the physical separation of gunpowder and matches, preventing an inevitable explosion,” says Dr Roy. “By knowing exactly how these gunpowder and matches are separated, we can develop new insights into how to stop the disease.”

The severity of Alzheimer's disease is assessed by the loss of functional neurons. There are two “tell-tale” signs of this disease: protein clots beta amyloid- the 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 Alzheimer's disease is caused by the formation and accumulation of beta-amyloid plaques, which trigger a cascade of molecular events leading to cell dysfunction and death. So this so-called "amyloid cascade hypothesis" places beta-amyloid at the center of the pathology of Alzheimer's disease.

Beta-amyloid requires interaction to form amyloid precursor protein(APP) and enzyme beta-secretase(BACE), which breaks down APP into smaller toxic fragments.

Top: bubbles containing APP(green)
And BACE(red) usually physically
separated. Bottom: after neuron stimulation,
increasing synthesis beta amyloid, 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 at high levels in the brain,” explains Dr. Roy, “and if they are allowed to interact continuously, we will all get Alzheimer's disease.”

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

“To separate these accomplices, nature seems to have come up with an interesting trick,” comments Dr. Roy.

In addition, it turned out that conditions that enhance the synthesis of beta-amyloid protein also enhance the interaction between 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 of APP and BACE-1. A study of autopsy brain samples from patients with Alzheimer's disease showed an increase in the physical proximity of these proteins, confirming the pathophysiological significance of this phenomenon.

The study's findings are critical because they illuminate some of the earliest molecular trigger events for 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 the 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 exciting thing is that we may be able to screen for molecules that can physically separate APP and BACE-1.”

Scientists at the University of Michigan have discovered a new beneficial property epigallocatechin gallate (EGCG) is a bioactive substance contained in green tea leaves. The results of their study show 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 new beneficial property of one of the molecules contained in green tea: it prevents the misfolding of specific brain proteins. The aggregation of these proteins, called metal-associated beta-amyloids, associated with Alzheimer's disease and others neurodegenerative diseases .

U-M Life Sciences Institute Associate Professor Mi Hee Lim, PhD, and an interdisciplinary team of scientists studied the effect of green tea extract on aggregate formation metal-associated amyloid beta 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 amyloid beta was reduced.

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

To gain insight into the structure of 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 amyloid beta monomers and dimers to form more compact peptide conformations than when bound to untreated EGCG amyloid beta. 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 from a lot of scientists,” says Dr. Lim, noting that EGCG and other flavonoids found in natural foods have long been recognized as powerful antioxidants. “We took an integrated approach. This is the first example of an interdisciplinary study that focused on structure, conducted by three scientists from three different fields of science.”

According to Lim, although small molecules metal-associated amyloid beta are 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 so complex, we think a combination of 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 so 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 inhibit the potential toxicity of aggregates containing proteins and metals in fruit flies.

Based on materials

Original article:

S.-J. Hyung, A. S. DeToma, J. R. Brender, 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 toward 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 permitted provided that the active hyperlink to the page is not blocked from indexing and is not prohibited for the robot to follow Alzheimer's disease. Written permission is required.

More about Alzheimer's disease

Kidney damage may be indicated by:

Proteinuria ( the appearance of protein in the urine). It is the first and most significant manifestation of kidney damage in amyloidosis. Normally, the protein concentration in the urine does not exceed 0.033 g/l, but if the integrity of the kidney filter is damaged, blood cells and large molecular proteins begin to be excreted in the urine. Proteinuria more than 3 g/l indicates severe nephrotic syndrome and severe damage to renal tissue.
Hematuria ( the appearance of red blood cells in the urine). Normally, during microscopic examination of urine, no more than 1–3 red blood cells are allowed per field of view. Blood in the urine may indicate the development of nephrotic syndrome or be a sign of inflammatory damage to the kidney 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-inflammatory disease of the kidneys or other organs of the genitourinary system.
Cylindruria ( the presence of casts in the urine). Cylinders are casts that are formed 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 red and white blood cells.
Decreased urine density. Normal urine density ranges from 1.010 to 1.022, however, with the destruction of the renal nephrons, the organ’s concentrating ability is markedly reduced, as a result of which the urine density will decrease.

Biochemical blood test

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

Diagnostic value for amyloidosis is:

proteins of the general phase of inflammation;
cholesterol level;
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 and prevent damage to healthy tissue.

Proteins of acute phase of inflammation

Protein	Normal values
Whey protein amyloid A(SAA)	Less than 0.4 mg/l.
*Alpha 2 globulin*	M: 1.5 – 3.5 g/l.
*Alpha 2 globulin*	*AND:* 1.75 – 4.2 g/l.
*Alpha 1-antitrypsin*	0.9 – 2 g/l.
*C-reactive protein*	No 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 often occurs in hereditary forms of amyloidosis, which must be taken into account when assessing this indicator.

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

Liver tests for liver amyloidosis

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

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 cells in the body. 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.

Blood protein levels
The normal level of total protein in the blood is 65 – 85 g/l. A decrease in this indicator can be observed with the development of nephrotic syndrome ( as a result of protein loss in urine), as well as in severe liver failure, since all the body’s 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 ( norm – 44 – 80 µmol/l in women and 74 – 110 µmol/l in men) is formed in muscle tissue, after which it enters the blood 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 renal dysfunction in amyloidosis.

Ultrasound examination of internal organs

This study allows us to assess the structure and structure of internal organs, which is necessary to assess the degree of dysfunction and determine the extent of the pathological process.

Ultrasound for amyloidosis can reveal:

Compaction and enlargement ( or decrease in the azotemic stage) kidney.
Presence of renal cysts ( what could cause secondary amyloidosis).
Enlargement and hardening of the liver and spleen, as well as disruption of 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, the largest artery in the body).
Accumulation of fluid in body cavities ( ascites, hydrothorax, hydropericardium).

Genetic research

Genetic testing is prescribed if hereditary amyloidosis is suspected ( that is, if it is not possible to confirm the secondary nature of the disease). Typically, polymerase chain reaction is used for this, the principle of which is to take genetic material from a sick person ( This is usually blood, urine, saliva or any other biological fluid) and the study of genes on certain chromosomes. Identification 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, genetic testing is recommended for all family members and close relatives of the patient to exclude the presence of this disease.

Biopsy

A biopsy is the intravital removal of a small piece of tissue or organ and its examination in the laboratory using special techniques. This study is the “gold standard” in the diagnosis of amyloidosis and can confirm the diagnosis in more than 90% of cases.

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

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

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

Treatment of amyloidosis

It is quite difficult to identify amyloidosis and begin treatment in the early stages of its development, since the disease clinically manifests itself decades after its onset. At the same time, in case of severe renal failure, therapeutic measures are ineffective and are of a supportive nature.

Is hospitalization necessary to treat amyloidosis?

If amyloidosis is suspected, hospitalization in the nephrology or therapy department is recommended in order to conduct a thorough examination of the genitourinary system, since kidney damage is the most common 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 the diagnostic process does not reveal serious functional disorders of any organs, further treatment can be carried out on an outpatient basis ( at home) provided that the patient strictly follows all the doctor’s instructions and comes for 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;
renal failure;
liver failure;
heart failure;
adrenal insufficiency;
severe anemia ( hemoglobin concentration less than 90 g/l);
hypersplenism;
internal bleeding.

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

In the treatment of amyloidosis the following is used:

drug treatment;
diet therapy;
peritoneal dialysis;
organ transplantation.

Drug treatment

Drug treatment is aimed at slowing down the process of amyloid formation ( if possible). Good effectiveness is 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 is the least susceptible to drug treatment.

Drug treatment of amyloidosis

Group of drugs	Representatives	Mechanism of therapeutic action	Directions for use and doses
*Steroidal anti-inflammatory drugs*	*Prednisolone*	They inhibit immune reactions and have a pronounced anti-inflammatory effect. They reduce the rate of formation of lymphocytes and also inhibit the migration of leukocytes to the site of inflammation, which is responsible for the positive effect in amyloidosis.	The dosage, duration of use and route of administration are selected individually in each case, depending on the severity of the underlying and concomitant diseases.
*Steroidal anti-inflammatory drugs*	*Dexamethasone*
*Antitumor drugs*	*Melphalan*	Disturbs 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 process of amyloid formation ( especially in the primary form of the disease).	Orally, 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 the cells of the human body, reducing the rate of formation of leukocytes and amyloidoblasts.	Orally, 500–750 mg daily or every other day. The duration of treatment is determined by the effectiveness and tolerability of the drug.
*Antigout drugs*	*Colchicine*	Inhibits the rate of formation of leukocytes and the process of synthesis of amyloid fibrils in amyloidoblasts. Effective for familial Mediterranean fever and to a lesser extent for secondary amyloidosis.	Orally 1 mg 2-3 times a day. Long-term treatment ( more than 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 a 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 effects 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 liquid ( 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 during nephrotic syndrome and at the same time reduce their consumption from food, since in case of renal failure the process of excretion of by-products of their metabolism is disrupted.

Diet for amyloidosis

What is recommended to eat?	What is not recommended to eat?
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 ( no salt); milk and fermented milk products; weak tea; freshly squeezed juices.	meat and fish products in large quantities; baked goods; 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), however there are certain differences. In peritoneal dialysis, the semi-permeable membrane through which metabolic by-products are removed is the peritoneum - a thin, well-supplied serous membrane lining the internal surface and organs of the abdominal cavity. The total area of the peritoneum is close to the surface area of the human body. A special solution is injected 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 that blood purification is slower than with hemodialysis.

The main advantages of this method over hemodialysis are:

Removal of B2-microglobulin, which can cause the development of amyloidosis.
Constant ( continuous) cleansing the blood of metabolic by-products.
Possibility of use in outpatient settings ( at home).

Execution technique
The catheter is installed in the operating room under local or general anesthesia. It is usually installed in the lower part of the abdominal wall, with only a small section of it extending out. About 2 liters of a special dialysate solution is injected into the abdominal cavity through a catheter, after which the catheter is tightly closed and the liquid 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 specified period of time ( usually every 6 – 8 hours) it is necessary to drain the “old” solution from the abdominal cavity and replace it with a new one. The entire 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;
for infectious skin diseases in the abdominal area;
for mental illness.

Organ transplant

Donor organ transplantation is the only means of saving the lives of patients with developed organ failure. However, it is worth remembering that this treatment method 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.

In case of amyloidosis, it is possible to transplant:

kidney;
liver tissue;
heart;
skin.

Donor organs can be obtained from a living donor ( except the heart), as well as from a corpse or from a person who has been diagnosed as brain dead, but the functional activity of the internal organs is maintained artificially. In addition, today there is an artificial heart, which is a fully mechanized device 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 the rejection of “foreign” tissue by one’s own body.

Complications of amyloidosis

The consequences of amyloidosis usually include various acute conditions that develop against the background of impaired functions of one or more organs. Often these complications cause the patient's death.

The most dangerous complications of amyloidosis are:

Myocardial infarction. When systemic blood pressure increases ( 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 heart tissue, which further impairs its blood supply. As a result, during sudden physical exertion or emotional stress, a discrepancy may develop between the need of the heart muscle for oxygen and the level of its delivery, which can lead to the death of cardiomyocytes ( heart muscle cells). If a person does not die immediately ( which is observed quite often), a scar forms in the area of the heart attack, which further “weakens” the heart ( because scar tissue is unable to contract) and can lead to chronic heart failure.
Stroke. A stroke is an acute disruption of the blood supply to brain tissue. In amyloidosis, the condition usually develops as a result of bleeding through a deformed blood vessel wall ( hemorrhagic stroke). As a result of nerve cells being soaked in blood, they die, which, depending on the area of the stroke, can manifest itself in a variety of symptoms - from impaired sensitivity and motor activity to the death of the patient.
Hepatic vein thrombosis. This complication can develop as a result of an increase in fibrinogen concentration ( blood coagulation protein) in the renal vein system, which leads to the formation of blood clots that clog the lumens of blood vessels. As a result, acute renal failure develops. The mechanism for the development of this complication is due to the fact that in nephrotic syndrome a large amount of albumin is released through the kidneys ( major blood plasma proteins), while fibrinogen remains in the blood and its relative concentration increases.
Infectious diseases. Depletion of protective systems, loss of large amounts of proteins in the urine and the development of multiple organ failure make the patient's body practically defenseless against various pathogenic microorganisms. Pneumonia is often reported with amyloidosis ( pneumonia), pyelonephritis and glomerulonephritis, skin infections ( erysipelas) and soft tissues, food toxic infections, viral infections ( for example, mumps) and so on.

Is pregnancy possible with amyloidosis?

Pregnancy with amyloidosis is possible only in cases where the functional activity of a woman’s vital organs is sufficient to carry and give birth to a child. Otherwise, the pregnancy may result in the death of both the fetus and the mother.

Some local forms of amyloidosis do not pose any danger to pregnancy. If amyloid accumulation 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 functions;
liver functions;
adrenal functions;
rate of amyloid formation.

Heart functions
A dangerous complication of amyloidosis is heart failure ( CH), developing due to the deposition of amyloid in the heart tissue. This leads to a disruption of its contractile activity, as a result of which certain symptoms appear during exercise - weakness, shortness of breath ( feeling of lack of air), rapid heartbeat, chest pain. Since bearing 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, there are 4 functional classes of HF. The first is characterized by the appearance of symptoms only during extremely heavy physical exertion, while the fourth is indicated for patients who cannot care for themselves. Women with functional class I - II can safely carry a child, but artificial delivery is recommended for them ( by caesarean section). In the presence of functional class III - IV, 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 for medical reasons).

Kidney functions
The developing fetus requires a constant supply of various nutrients, including proteins. However, when amyloid is deposited in the mother's kidneys, the kidney tissue is destroyed, 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 proteins ( being the main building material for a growing organism), as a result of which developmental delays may occur, and after birth, developmental defects, growth retardation, mental and mental disorders may be observed.

The extreme level of kidney damage associated with amyloidosis is chronic renal failure, in which the kidneys are unable to remove metabolic byproducts from the body. As a result of this, 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 intrauterine 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 so-called portal vein system, which collects blood from all unpaired organs of the abdominal cavity ( from the stomach, intestines, spleen and others). 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. The result of this may be developmental delay, various congenital anomalies, and with severe tense ascites ( if the amount of liquid exceeds 5 - 6 liters) intrauterine fetal death may occur.

Functions of the adrenal glands
Under normal conditions, the adrenal glands secrete certain hormones that are involved in the regulation of metabolic processes in the body. When affected by amyloidosis, the amount of functional tissue in these organs decreases, resulting in a noticeable 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 weakly expressed 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
Typically, this process proceeds rather slowly, which is why 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, developing against the background of chronic purulent-inflammatory processes in the body) amyloid is formed very quickly. This may result in amyloid infiltration of placental vessels ( organ that ensures metabolism between mother and fetus), which will lead to oxygen starvation of the fetus, delayed development, or even intrauterine death.

Does amyloidosis occur in children?

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

Amyloidosis in children can be caused by:

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 defective genes from both parents. If a child receives a defective gene from one parent, and a normal one from the other, 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 manifests itself as generalized amyloidosis, which develops in the first 10 years of life. Kidney tissue is predominantly affected. In addition to amyloidosis, attacks of fever are observed ( increased body temperature, chills, increased sweating) and mental disorders.
English amyloidosis. It is characterized by predominantly kidney damage, as well as attacks of fever and hearing loss.
Portuguese amyloidosis. The clinical picture is dominated by damage to the nerves of the lower extremities, which is manifested by a crawling sensation, impaired sensitivity and movement disorders. The prognosis for life is favorable, but paralysis often develops ( inability to perform voluntary movements).
American amyloidosis. Characterized by predominant damage to the nerves of the upper extremities. Clinical manifestations are the same as for 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 - 10 ( and sometimes less) years, the first signs of generalized amyloidosis will begin to appear. The prognosis in this case is extremely unfavorable - multiple organ failure develops quite quickly and death occurs. The treatment given produces positive results only in half of the cases and for a short period of time, after which the disease usually recurs ( worsens again).

Is there effective prevention of amyloidosis?

The 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 relapse of the disease) is ineffective and does not give the desired results.

Prevention of amyloidosis

Form of amyloidosis	Brief description	Preventive measures
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 ( There are only 23 pairs of them in the human genetic apparatus). These genes are passed on from generation to generation, as a result of which all the offspring of a sick person with a certain degree of probability may develop amyloidosis. Defective genes trigger the formation of mutant cells ( amyloidoblasts), synthesizing fibrillar proteins, which are subsequently converted into amyloid and deposited in the tissues of the body.	Since the disease occurs even when a child is conceived ( when 23 maternal and 23 paternal chromosomes merge), postnatal prevention ( carried out after the birth of a child) is ineffective. The only effective measure is genetic research of the fetus in the early stages of intrauterine development ( up to 22 weeks of pregnancy). If genes responsible for the development of amyloidosis are identified, termination of pregnancy is recommended for medical reasons. If any of the person’s immediate relatives had amyloidosis, he and his spouse ( spouse) it is also recommended to undergo genetic testing in order to identify the latent form of the disease ( carrier status).
*Secondary amyloidosis*	The development of this form of the disease occurs during a 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 of timely and complete treatment of chronic inflammatory and purulent processes in the body. This is done through the use of broad-spectrum antibacterial drugs ( penicillins, ceftriaxone, streptomycin, isoniazid and others) until the clinical and laboratory manifestations of the disease disappear, as well as for a certain period of time after complete recovery.

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 unfavorable - more than half of patients die within the first year after diagnosis. However, it is often possible to diagnose the disease earlier. 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. If renal failure develops, the patient dies within a few months. Hemodialysis ( blood purification using a special device) prolongs the patient’s life by 5 years or more. Kidney transplantation can be an effective treatment, but amyloid deposits in the donor organ are observed in more than half of cases.
Liver function. With severe portal hypertension ( increased pressure in the portal vein system) 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.
Heart function. With the development of stage VI heart failure, most patients die within 6 months. Heart transplant can prolong the life of patients ( provided that other organs and systems are functioning normally).
Bowel function. With intestinal amyloidosis, malabsorption can reach extreme severity. In the absence of specific treatment ( complete intravenous nutrition) the patient's death 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 manifests itself as damage to all organs and tissues, rapid development of multiple organ failure and death of the patient. A year after diagnosis, only 51 out of a hundred people are still 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 unfavorable. Death usually occurs due to kidney failure within a few years of diagnosis.
Secondary amyloidosis. The prognosis is determined by the functional state of the internal organs. The main cause of death in this form of the disease is also chronic renal failure.

Local ( local) forms of amyloidosis usually present as tumor-like formations of various sizes ( from 1 – 2 to tens of centimeters in diameter). As they grow, they can put pressure on neighboring organs, but timely surgical treatment can eliminate the disease. There is virtually no threat to life.

Is it possible to cure amyloidosis with folk remedies?

There are traditional methods that have been used for many years in the treatment of this disease. However, it is worth noting that self-medication for such a serious disease as amyloidosis can lead to the most undesirable consequences, therefore, before starting to use traditional recipes, it is strongly recommended to consult a doctor.

For amyloidosis you can use:

Herbal anti-inflammatory infusion. Contains fresh wild chamomile flowers ( have anti-inflammatory and antimicrobial effects), immortelle flowers ( have an anti-inflammatory effect and also improve the secretion of bilirubin with bile), St. John's wort herb ( 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 this, close the lid tightly and leave in a dark place for 5 - 6 hours. Take 200 ml 1 time per day before bedtime. The duration of continuous treatment is no more than 3 months.
Infusion of rowan and blueberry fruits. 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 of dead nettle. This plant contains tannins, ascorbic acid, histamine and many other substances. Used for chronic infectious kidney diseases. To prepare the infusion, 3–4 tablespoons of crushed nettle herb should be poured into a thermos with 500 milliliters of hot water ( not boiling water) and take 100 milliliters 4 – 5 times a day.
Infusion of juniper fruits. It has anti-inflammatory, antimicrobial, choleretic and diuretic effects. To prepare the infusion, pour 1 tablespoon of dried berries into 1 liter of boiling water and leave in a dark place for 2 to 4 hours. Take 1 tablespoon 3-4 times a day before meals.
Oat grass tincture. It has anti-inflammatory and general tonic effects. Increases the body's performance and resistance to stress. To prepare the tincture, you need to pour 200 mg of crushed oat grass with 70% alcohol and leave in a dark place for 3 weeks, shaking the jar daily. After this, strain and take 1 teaspoon 3 times a day, diluting in 100 ml of warm boiled water.

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, a postdoctoral fellow at Northwestern Feinberg University's Cognitive Neurology and Alzheimer's Disease Center, there is unprecedented evidence that amyloid is beginning to accumulate in the brain. in the human brain from a young age. According to Geul, this is of great importance, since it is known that if amyloid is in the human body for a long time, 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 are essential for maintaining memory and attention.

Geula and his colleagues examined neurons obtained from the brains of three different groups of patients - 13 cognitively healthy people aged 20-66 years, 16 elderly people 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 the pathological processes of 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:

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 may 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.” In the iDISCO technique, the brain is soaked in a compound that gives fats an electrical 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 clinical trials of drugs under development fail: because they have different effectiveness for different types of the disease. 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

In the early stages of Alzheimer's disease, a person's brain may reorganize itself in special ways that delay 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 area?

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