Unexpected results from the Scripps Research Institute and ModGene, LLC may completely change scientists' understanding of Alzheimer's disease - one of the most common human neurodegenerative diseases - by pointing to the liver instead of the brain as a source of amyloid peptides deposited as brain plaques. with this devastating disease. This discovery offers a relatively simple approach to the treatment and prevention of Alzheimer's disease.

To determine the genes that affect the amount of amyloid protein accumulated in the brain, the scientists used a mouse model of Alzheimer's disease. They identified three genes that protect against the deposition and accumulation of amyloid in the brains of animals. The mouse brain was protected by a decrease in the expression of each of these genes in liver cells. One of them codes for presenilin, a cell membrane protein thought to contribute to the development of Alzheimer's disease.

"This unexpected finding opens the door to the development of new treatments for Alzheimer's disease," said study lead researcher Professor Gregor Sutcliffe. "It could greatly facilitate the development of methods for its treatment and prevention."

An estimated 5.1 million Americans suffer from this neurodegenerative disease, including almost half of those aged 85 and over. If science does not find a way to prevent its development and effective treatments, by 2050 the number of patients aged 65 years and over will vary from 11 to 16 million. In addition to human suffering, this is a huge economic burden. A new report from the US Alzheimer's Association shows that in the absence of positive interventions for the disease, the cumulative cost of caring for Alzheimer's patients between 2010 and 2050 will be $20 trillion.

In search of a solution to the Alzheimer's puzzle, Sutcliffe and his collaborators have focused in the past few years on naturally occurring differences in neurological disease susceptibility in different strains of mice, building up a vast database of gene activity in various tissues. These data provide maps of trait expression that can be superimposed on maps of disease modifier genes.

As with almost all scientific discoveries, Sutcliffe's research builds on earlier data. A few years ago, researchers at Case Western Reserve University mapped three genes that modify the accumulation of abnormal beta-amyloid in the brains of transgenic Alzheimer's mice in large regions of chromosomes, each containing hundreds of genes. Using crosses of mouse lines B6 and D2, they studied more than 500 of their descendants.

Based on the results of this study, Sutcliffe applied his gene expression databases to a mouse model of Alzheimer's disease, looking for differences in gene expression that correlated with differences in disease susceptibility between the B6 and D2 strains. This intensive work involved creating computer programs that identified each genetic difference between the B6 and D2 genomes and performing a mathematical analysis of their correlation (known as regression analysis). Correlations were made between genotypic differences (B6 and D2) and the amount of messenger RNA produced from more than 25,000 genes in a given tissue in 40 recombinant inbred mouse strains. These correlations were calculated for 10 types of tissues, one of which was the liver.

“One of the key aspects of this work was learning how to question massive databases to collect information about the identity of inherited modifier genes,” Sutcliffe says. “This was new and, in a sense, groundbreaking work: we were inventing a new way to identify modifier genes, combining all these steps and automating the process. We realized that it is possible to learn how the pathogenic transgenic effect is modified without studying the transgenic mice themselves.”

The gene hunt has identified good candidates for each of the three modifier genes discovered by Case Western scientists, and one of those candidates, a mouse gene corresponding to a human gene, one of whose variants predisposes to early onset Alzheimer's disease, was of particular interest to scientists. .

"The product of this gene, the protein presenilin 2, is part of an enzyme complex involved in the formation of pathogenic amyloid beta," explains Sutcliffe. “Suddenly, the inherited expression of presenilin 2 was found in the liver and not in the brain. More active expression of presenilin 2 in the liver correlated with greater accumulation of beta-amyloid in the brain and the development of pathology consistent with Alzheimer's disease.

This discovery suggested that significant concentrations of beta-amyloid could originate in the liver, circulate in the blood, and reach the brain. If this is true, blocking the production of beta-amyloid in the liver could protect the brain.

To test this hypothesis, Sutcliffe and his colleagues set up an in vivo experiment using wild-type mice, since they most accurately reproduce the environment in which natural beta-amyloid synthesis occurs. "We figured that if brain amyloid is produced in the liver and carried to the brain in the blood, then it could be seen in all mice," Sutcliffe says, "and predictably in humans."

The mice were injected with imatinib (trade name Gleevec, an FDA-approved anti-cancer drug), a relatively new drug currently approved for the treatment of chronic myeloid leukemia and gastrointestinal tumors. The drug sharply reduces the synthesis of beta-amyloid in neuroblastoma cells transfected with amyloid precursor protein (APP), as well as in cell-free extracts obtained from transfected cells. Importantly, Gleevec does not cross the blood-brain barrier well in both mice and humans.

“It was this property of the drug that determined our choice,” explains Sutcliffe. "Because it does not cross the blood-brain barrier, we were able to focus on amyloid synthesis outside the brain and how this synthesis might contribute to the accumulation of amyloid in the brain, where it is associated with disease."

Mice were injected with Gleevec twice a day for seven days. Plasma and brain tissue were then taken and the amount of beta-amyloid in the blood and brain was measured. The result: the drug drastically reduced the amount of beta-amyloid not only in the blood, but also in the brain, where it could not penetrate. Thus, a significant portion of brain amyloid must have been synthesized outside of the brain, and imatinib is a candidate drug for the prevention and treatment of Alzheimer's disease.

As for the future of this research, Sutcliffe hopes to find a partner and investors to conduct clinical trials and develop new drugs.

Violations of fat metabolism in the body go unnoticed for a long time, but sooner or later leads to negative consequences. If the appearance of xanthomas (cholesterol plaques on the body) is not dangerous, and rather refers to a cosmetic defect, then vascular atherosclerosis is a serious problem requiring treatment. For the almost asymptomatic course and formidable complications, the disease received an unofficial name - an affectionate killer. Is it possible to dissolve already formed plaques on the vessel wall, and how to do it: let's try to figure it out.

Why plaques are deposited on the vessels

The appearance of cholesterol plaques on the body or the inner wall of blood vessels is always associated with metabolic disorders. The exact cause of the development of the disease by physicians has not yet been named, and several hypotheses are put forward in the scientific world:

1. Lipoprotein infiltration - the deposition of cholesterol in the walls of arteries and arterioles occurs primarily, i.e. for no specific reason.
2. The theory of primary dysfunction of the endothelium - here damage to the vascular wall comes to the fore, and only then the deposition of cholesterol molecules.
3. The autoimmune theory connects the process of formation with disorders of the cellular link of immunity - an attack by leukocytes and macrophages of the vascular endothelium.
4. The monoclonal hypothesis explains the disease by the primary appearance of a pathological clone of smooth muscle tissue cells, which is able to "attract" cholesterol molecules to itself.
5. Some scientists find a connection in the development of pathology and the primary damage to the walls of blood vessels by viral particles (CMVI, herpes, etc.).
6. The peroxide hypothesis speaks of a violation of the antioxidant systems of the body and the processes of lipid peroxidation.
7. Hormonal hypothesis - according to it, the increased functional activity of the pituitary gland can lead to an increase in the synthesis of building materials for cholesterol in the liver.
8. The genetic hypothesis speaks of a hereditary defect in the vascular endothelium.

Despite various assumptions, scientists agree that the development of the disease is influenced, first of all, by lifestyle and diet. The provoking factors that can cause atherosclerosis include:

• smoking;
• high level of total cholesterol in the blood (> 5.1 mmol / l);
• persistent hypertension, in which blood pressure is higher than 140/90 mm Hg. Art.;
• metabolic diseases (diabetes mellitus, hypothyroidism, metabolic syndrome, etc.);
• postmenopausal women;
• obesity (BMI over 30);
• physical inactivity, minimal physical activity;
• stress, regular emotional overstrain;
• non-compliance with the principles of proper nutrition.

What are cholesterol plaques and how do they form? There are several successive stages in the pathogenesis of atherosclerosis:

1. The appearance of fatty spots on the vascular endothelium. Atherogenic cholesterol fractions, freely circulating in the blood, bind to proteoglycans on the inner wall of predominantly small vessels and are deposited in a thin layer on the endothelium.
2. Liposclerosis is an increase in the thickness and size of the plaque. At this stage, the fat spot grows into the connective tissue, and even more lipids are deposited on it.
3. Atheromtosis - germination of plaque in the muscular layer of the artery. Fat deposits become even more voluminous, they damage the endothelium and grow deeper into the thickness of the vessel.
4. Atherocalcinosis is a thickening of a cholesterol plaque. The thickness of fatty deposits grows, calcifications are deposited in them. The plaque becomes very dense and significantly narrows the lumen of the vessel, causing circulatory disorders.

What are plaques

It is important to understand that the disease in question is associated with multiple metabolic disorders. This process affects the entire body. At the same time, depending on the clinically significant localization, atherosclerosis is distinguished:

• aorta;
• coronary (heart) arteries;
• vessels of the brain;
• kidney arteries;
• vessels of the lower extremities.

Atherosclerosis of the aorta - the largest vessel in the human body - is asymptomatic for a long time and can only be detected during an examination (for example, aortocardiography). Occasionally, patients are concerned about non-intense pressing, relieving pain in the chest or abdomen. The characteristic signs of the disease also include shortness of breath, arterial hypertension (an increase in pressure occurs mainly due to systolic, "upper").

Cholesterol plaques often affect the coronary arteries. Violation of the blood supply to the heart muscle quickly leads to a clinical picture of typical angina pectoris - pressing pains in the chest during physical activity, shortness of breath, an inexplicable feeling of fear of death. Over time, the frequency of seizures increases, and the patient develops signs of heart failure.

The predominant lesion is called. This pathology is common in older people and manifests itself:

• fatigue;
• decrease in working capacity;
• a sharp deterioration in memory;
• increased excitability;
• irritability;
• sharpening of personal and personality traits: for example, a thrifty person becomes greedy, a self-confident person becomes selfish, selfish, etc .;
• insomnia;
• headache;
• dizziness;
• noise in the head/ears.

With the predominant deposition of cholesterol on the walls of the renal vessels, there is a persistent increase in blood pressure (mainly due to diastolic, “lower”) and progressive signs of insufficiency of the organs of the urinary system: edema, dysuria, and nagging pain in the lumbar region.

It occurs a little less frequently. It is manifested by pain in the calf muscles, which are aggravated by prolonged walking (the so-called intermittent claudication). Lack of timely treatment leads to the development of a trophic ulcer, and then gangrene of the leg.

In addition to the vascular wall, cholesterol is often deposited in. Such plaques are called xanthoma (xanthelasma). They look like flat or yellowish wen, slightly raised above the surface of healthy skin.

Why are atherosclerotic plaques dangerous?

The danger of atherosclerosis is not in damage to the vascular wall, but in formidable complications that are caused by circulatory disorders. Through the narrowed arteries, blood is hardly supplied to the internal organs, and the patient develops acute or chronic conditions associated with a lack of oxygen and nutrients. First of all, systems that work intensively throughout life and need constant replenishment of energy reserves suffer - the heart and brain.

Common complications of atherosclerosis include:

• acute myocardial infarction;
• cardiac ischemia;
• chronic heart failure;
• stroke - stroke;
• encephalopathy;
• gangrene of the lower extremities.

That is why the treatment of atherosclerosis is one of the priorities of modern healthcare. And how is this disease treated, and are there any means that can dissolve existing cholesterol plaques?

How to remove atherosclerotic plaque

Treatment of atherosclerosis is a long process that requires the cooperation of the patient and his doctor. In order for the dissolution of cholesterol plaques to be as effective as possible, it is important not only to take pills, but also to pay attention to your lifestyle and diet. Effective, according to the majority of patients, are the means of traditional medicine.

Diet and lifestyle: what the patient needs to know

Lifestyle correction is the first thing you should pay attention to a person who has been found to have atherosclerotic plaques. Non-drug methods for lowering blood cholesterol levels and treating atherosclerosis include:

1. Normalization of body weight (with obesity).
2. Dosed physical activity in conditions of sufficient oxygen supply. The volume of loads should be agreed with the attending physician, based on the degree of vascular damage and the presence of concomitant diseases.
3. Refusal/sharp restriction of alcohol consumption. It has been proven that strong drinks cause an increase in dyslipidemia, provoking an increase in triglycerides.
4. To give up smoking. Nicotine not only increases the risk of cardiovascular pathology, but also contributes to damage to the arterial endothelium, which triggers a chain of pathological processes in the formation of cholesterol plaques.
5. Exclusion of stress and any traumatic situations, both at work and at home.

Patients with atherosclerosis should pay special attention to their diet. The therapeutic diet is designed to lower blood cholesterol levels and reduce the risk of atherosclerotic plaque formation in the future.

1. Limit animal fats, which are the main dietary sources of cholesterol. The leaders in the content of "bad" lipids are lard, beef fat, brains, kidneys and other offal, fatty red meat, hard cheeses, etc.
2. The basis of the diet should be vegetables and fruits, fiber (dietary fiber). They help improve digestion and normalize metabolism.
3. The calorie content of the daily diet is selected in accordance with the patient's loads and motor activity.
4. Refusal of such a cooking method as frying. All dishes are steamed, boiled or stewed.
5. It is advisable to replace red meat (beef, lamb, pork) with sea fish at least 2-3 times a week. Fatty fish is useful for atherosclerosis due to the high content of "good" cholesterol - high density lipoproteins.

Note! At an early stage of atherosclerosis, it is enough for the patient to lead a healthy lifestyle and eat right: cholesterol levels will decrease even without taking pills.

Medications for plaque formation

If non-drug treatments are ineffective for 3 months or more, the doctor may prescribe pills to the patient that lower blood cholesterol levels and dissolve existing atherosclerotic plaques.

To include:

• statins;
• fibrates;
• bile acid sequestrants;
• inhibitors of absorption (absorption) of cholesterol in the intestine;
• omega 3.6.

Statins (Atorvastatin,) are the most popular group of lipid-lowering drugs today. They have the following pharmacological action:

1. Decreased production of cholesterol in liver cells.
2. Reducing the content of atherogenic lipids in the intracellular fluid.
3. Increased destruction and excretion of fat-like substances from the body.
4. Reducing the severity of inflammation of the endothelium.
5. Prevention of damage to new sections of the vascular wall.

According to statistics, the drugs of the group increase the life expectancy of patients with atherosclerosis, significantly reduce the risk of complications and deep damage to blood vessels. Statins also have their drawbacks: they cannot be prescribed for laboratory-confirmed liver diseases (with ALT 3 or more times higher than normal) due to hepatotoxicity.

- antilipidemic drugs that reduce the level of "bad" cholesterol and increase the concentration of "good". May be given in combination with statins.

The action of bile acid sequestrants and cholesterol absorption inhibitors is based on the binding of molecules / preventing the absorption of fatty alcohol in the intestine and removing them from the body in a natural way. Common side effects of this group of drugs are bloating, loose stools.

Omega-3.6 are popular dietary supplements containing anti-atherogenic cholesterol fractions. They help to reduce the level of "bad" LDL and VLDL in the blood, as well as cleanse the vascular walls from already formed plaques.

Surgical methods of cleaning vessels from plaques

With a pronounced circulatory disorder in the vessels filled with plaques, it is possible to carry out one of the methods of surgical correction of the condition:

• balloon angioplasty - percutaneous injection of a small balloon into the cavity of the affected vessel, which is then inflated to expand the lumen of the artery;
• stenting - the introduction of a stable all-metal frame into the site of blockage of the stent;
• shunting - "switching off" the narrowed artery and creating an alternative source of blood supply to the internal organs through the collaterals.

Can traditional medicine help?

And remain popular in the treatment of atherosclerosis and the dissolution of cholesterol plaques. Remember that any of them can be taken only after consulting a specialist.

Common alternative medicine recipes include:

1. Daily intake in the morning on an empty stomach 1 tbsp. l. vegetable (olive, linseed, pumpkin) oil.
2. The use of a medicinal mixture of equal parts of vegetable oil, honey, lemon juice.
3. Treatment with tincture of Japanese Sophora (for 1 cup of crushed pods - 500 ml of vodka). The mixture, which has been infused for 3 weeks, is filtered and taken according to Art. l. × 3 r / day. for 3-4 months.
4. Use of dill seeds. Prepare an infusion of 1 tbsp. l. dried seeds and 200 ml of boiling water. Accept according to Art. l. 4-5 days. The course of treatment is long, at least 2 months.
5. Daily intake of freshly squeezed potato juice.
6. Application of lemon-garlic mixture. Grate the head of garlic and the whole lemon (with the peel) on a fine grater. Mix the resulting slurry and pour water for a day. Take 2 tbsp. l. the resulting liquid 2 r / d.

Thus, medicine has not yet come up with a magic pill that will help you quickly and permanently get rid of atherosclerosis. Treatment of the disease is a long and difficult process that requires maximum efficiency from both the doctor and the patient. Only an integrated approach will achieve the health of the cardiovascular system and longevity.

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.

"This molecule has received a lot of interest from many scientists," says Dr. Lim, noting that EGCG and other flavonoids found in natural foods have long been considered powerful antioxidants. “We took an integrated 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.

More about Alzheimer's disease

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 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 highly expressed in the brain," explains Dr. Roy, "and if you let them interact continuously, we'll all get Alzheimer's."

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."

Amyloidosis- a group of diseases (forms), a common feature of which is the deposition in organs and tissues of a special protein of the b-fibrillar structure.
Amyloid in tissues appears either around collagen fibers (pericollagenic amyloidosis) or on basement membranes or around reticular fibers (perireticular amyloidosis).

Epidemiology. The frequency in the population is at least 1:50,000. Some clinical forms of amyloidosis are noted in certain areas of the globe: for example, Mediterranean familial fever or familial amyloid polyneuropathy (the latter is common in Japan, Portugal, Sweden, Italy).
Amyloidosis is more often detected in the second half of life.

Classification Nomenclature Committee of the International Union of Immunological Societies (WHO Bulletin, 1993).
- AL-amyloidosis (A - amyloidosis, amyloidosis, L - light chains, light chains) - primary, associated with multiple myeloma (amyloidosis is recorded in 10-20% of cases of multiple myeloma).
- AA-amyloidosis (acquired amyloidosis, acquired amyloidosis) - secondary amyloidosis against the background of chronic inflammatory diseases, as well as with familial Mediterranean fever (periodic illness).
- ATTR-amyloidosis (A - amyloidosis, amyloidosis, TTR - transthyretin, transthyretin) - hereditary familial amyloidosis (familial amyloid polyneuropathy) and senile systemic amyloidosis.
- Ab2M-amyloidosis (A-amyloidosis, amyloidosis, b2M - b2-microglobulin) - amyloidosis in patients undergoing planned hemodialysis.

Localized amyloidosis often develops in people of senile age (AIAPP-amyloidosis - in non-insulin-dependent diabetes mellitus, AV-amyloidosis - in Alzheimer's disease, AANF-amyloidosis - senile atrial amyloidosis).

Pathogenesis and pathomorphology. Modern concepts of amyloidogenesis suggest the production of a specific amyloid precursor protein under the influence of the so-called amyloid-releasing factor, produced by macrophages due to a genetic defect under the influence of a stimulating agent. The formation of AA from SAA is carried out by incomplete cleavage by proteases associated with the surface membrane of monocyte-macrophages.
The polymerization of soluble AA protein into fibrils also occurs on the surface of macrophages by the mechanism of cross-linking of polypeptides with the participation of membrane enzymes.
An experiment with casein amyloidosis in mice showed an important role in the induction of AA deposits of the so-called amyloid-accelerating factor, which is formed during inflammation in the spleen and liver. ATTR-amyloidosis includes familial amyloid polyneuropathy (less often cardiopathy and nephropathy) with an autosomal dominant mode of inheritance and systemic senile amyloidosis. The serum protein precursor of amyloidosis in this group is a component of the prealbumin molecule - transthyretin (transthyretin - TTR) - a transport protein for thyroxine and retinol, primarily synthesized in the liver. Hereditary familial amyloidosis is the result of a mutation in the gene responsible for the synthesis of the transthyretin molecule. The mutant transthyretin has a point substitution in the molecule. It is assumed that familial hereditary amyloidosis may be based on mutant forms of other proteins. Fibrils form the basis of amyloid deposits.
Purified amyloid derived from fibrils is a protein. In renal amyloidosis, the glomeruli are primarily affected, although amyloid is also found in the interstitial, peritubular, and vascular regions. In the early stages, amyloid is deposited as small foci in the mesangium and along the basement membrane.
As the disease progresses, the glomeruli are intensively filled with amyloid masses and their capillary bed is reduced.

clinical picture.
Very often, amyloidosis is asymptomatic for a long time.
The nature of clinical manifestations depends on the biochemical type of amyloid, the localization of amyloid deposits, the degree of their prevalence in the organs, the duration of the disease, and the presence of complications. As a rule, a complex of symptoms associated with damage to several organs is observed. Signs of kidney involvement (renal amyloidosis proper) are typical of AA and AL amyloidosis, they are not noted in familial amyloid polyneuropathy and Alzheimer's disease.
Clinical manifestations of amyloidosis of the kidneys vary from mild proteinuria to advanced NS: massive proteinuria, hypoproteinemia, hyperlilidemia (hypercholesterolemia, disorders of LP balance, increased content of E-LP and triglycerides), edematous syndrome.
Edema may not be present with adrenal amyloid infiltration and hyponatremia.
AH develops in 20-25% of cases, mainly with long-term AA amyloidosis.
Among the concomitant tubular dysfunctions, canal acidosis and renal diabetes are observed.
Against the background of amyloidosis of the kidneys, the development of thrombosis of the renal veins is possible.
Amyuidosis of the heart can develop with AL amyloidosis, rarely with AA amyloidosis; it usually presents with restrictive cardiomyopathy. The most common clinical manifestations: cardiomegaly, heart failure, various arrhythmias.
Effusive pericarditis is rare.
Localized atrial amyloidosis is often seen in people over 80 years of age.

Damage to the gastrointestinal tract is explained either by the direct involvement of organs in the amyloid process, or by indirect changes due to amyloid infiltration of regional nerve fibers.
Amyloidosis of the esophagus occurs more often simultaneously with lesions of other parts of the digestive system. Characterized by dysphagia when swallowing dense and dry food, especially when eating lying down, belching. On x-ray examination, the esophagus is hypotonic, peristalsis is weakened, when the patient is examined in a horizontal position, the barium suspension lingers in the esophagus for a long time.
Complications: amyloid ulcers of the esophagus and esophageal bleeding.
Amyloidosis of the stomach is usually combined with amyloidosis of the intestine and other organs. Clinical picture: feeling of heaviness in the epigastric region after eating, dyspeptic disorders; x-ray examination - smoothness of the folds of the mucous membrane, weakening of peristalsis and evacuation of contents from the stomach.
Complications: amyloid gastric ulcers, gastric bleeding, perforation of ulcers.

Differential Diagnosis carried out with chronic gastritis, gastric ulcer, less often with a tumor.
Biopsy data (detection of amyloidosis) are of decisive importance. Intestinal amyloidosis is a common localization of this disease. Manifested by a feeling of discomfort, heaviness, less often moderate dull or spastic pain in the abdomen, stool disorders: constipation or persistent diarrhea.

Coprological examination reveals severe steatorrhea, amylorrhea, creatorrhea. In the blood, anemia, leukocytosis, increased ESR, hypoproteinemia (due to hypoalbuminemia), hyperglobulinemia, hyponatremia, hypoprothrombinemia, hypocalcemia.
Special research methods detect violations of parietal digestion and absorption in the intestine.
An x-ray examination is characterized by unfolding (“raising up”) of intestinal loops, thickening of the folds and smoothness of the relief of the intestinal mucosa, slowing down or accelerating the passage of barium suspension through the intestines.

A biopsy of the mucous membrane of the small and large intestines confirms the diagnosis and allows for differential diagnosis with enteritis and colitis, especially with ulcerative colitis. Isolated tumor-like amyloidosis of the intestine proceeds under the guise of a tumor (pain, intestinal obstruction) and is usually found already on the operating table.

Complication: severe hypoproteinemia due to impaired intestinal absorption, polyhypovitaminosis, intestinal stenosis, amyloid ulcers, intestinal bleeding, perforation.

Hepatic amyloidosis is relatively common.
Characterized by an increase and compaction of the liver, on palpation its edge is smooth, painless. Often the syndrome of portal hypertension, ascites. Less common are pain in the right hypochondrium, dyspeptic symptoms, splenomegaly, jaundice, hemorrhagic syndrome.

Laboratory research determine the change in protein-sedimentary samples, hyperglobulinemia, hypercholesterolemia, in some cases - hyperbilirubinemia, increased activity of alkaline phosphatase, serum aminotransferases; positive test with bromsulfalein.
Of decisive importance in the diagnosis is a puncture biopsy of the liver. Complications: liver failure (in 7% of cases).

Amyloidosis of the pancreas is rarely diagnosed (occurs under the guise of chronic pancreatitis); characterized by dull pain in the left hypochondrium, dyspeptic symptoms, pancreatogenic diarrhea, steatorrhea.
The study of duodenal contents reveals exocrine pancreatic insufficiency.
In severe cases, secondary diabetes mellitus develops.

Skin lesions have the appearance of translucent waxy papules or plaques on the face, neck, in areas of natural folds.
Periorbital ecchymosis ("raccoon eyes") has been described.
Itching is not typical. Plaque hemorrhages are possible.
In some cases, there are dense swelling on the fingers, resembling scleroderma.

Mental disorders in the form of dementia are noted in localized forms of amyloidosis (Alzheimer's disease).

Hemorrhagic syndrome can develop in AL-amyloidosis due to deficiency of coagulation factor X, which has an affinity for amyloid fibrils.

Diagnostics.
Laboratory research.
Analysis of urine. Proteinuria ranges from microalbuminemia to massive proteinuria associated with NS. Hematuria is rare, leukocyturia is not massive and is not associated with concomitant infection ("meager changes in urinary sediment"). Cylinders are hyaline, waxy, rarely granular; they do not have metachromasia when stained, but give a sharply positive PAS reaction.
Due to massive proteinuria, hypoproteinemia occurs (due to hypoalbuminemia).
Leukocytosis is possible, an increase in ESR is characteristic.
Anemia accompanies CRF or is associated with a chronic inflammatory process. A kidney biopsy in the early stages of amyloidosis reveals amorphous hyaline masses in the mesangium, as well as a thickening of the basement membrane.
Further, diffuse extracellular eosinophilic material is found, stained with Congo red with a specific green birefringence when examined under a polarized microscope. Immunofluorescence shows a weak Ig fluorescence because the amyloid fibrils (in AL-amyloidosis) contain variable regions of the light chains. EM reveals characteristic non-branching amyloid fibrils with a diameter of 7.5–10 nm. Deposits of amyloid masses are found not only in the glomeruli, but also in the interstitium.

ultrasound. The size of the kidneys is enlarged or normal.
Functional tests with Congo red or methylene blue (rapid disappearance of intravenous dyes from the blood serum due to their fixation by amyloid, as well as a significant decrease in their excretion by the kidneys) are of historical importance due to low information content. It is necessary to assume the development of amyloidosis when proteinuria is detected in patients at risk (with RA, multiple myeloma, BEB, tuberculosis and leprosy).

In hereditary-familial syndromes, manifested by peripheral neuropathy, nephropathy, cardiomegaly, amyloidosis should be excluded. Treatment. Tasks: restriction of the synthesis of amyloid precursor (colchicine); inhibition of amyloid synthesis and prevention of its deposition in tissues; lysis of tissue amyloid structures.

Treatment background disease (chronic inflammation, RA) is necessary.
With active treatment of RA with cytostatics (cyclophosphamide, chlorambucil, azathioprine, methotrexate), amyloidosis occurs less frequently, and with already developed amyloidosis, a decrease in the severity of its clinical manifestations is observed - stabilization of renal function and a decrease in proteinuria. Primary amyloidosis and multiple myeloma are treated with chemotherapy (eg, combination therapy with melphalan and prednisolone).
However, its lack of efficacy and high toxicity lead to the search for new methods of treatment.

Among the latest developments in this direction are anthracycline and iododokeorubicin, which bind to AL-amyloid and promote its resorption.

Colchicine. In familial Mediterranean fever, the use of colchicine in the early stages delays the development of nephropathy, but it has a worse effect on already formed renal amyloidosis.

The effect of colchicine in secondary AA amyloidosis of the kidneys is being studied.
In the early stages of AA amyloidosis, an attempt to treat with aminoquinoline derivatives (chloroquine 0.25-0.5 g / day for a long time) is acceptable, but its effectiveness has not been proven in controlled studies.

Oral dimethyl sulfoxide is suggested for the treatment of amyloidosis.
The initial dose is 1% dimethyl sulfoxide solution, 10 ml 3 times a day. With good tolerance, the dose is gradually increased to 100-200 ml of a 3-5% solution per day.

Treatment regimens for primary amyloidosis.
- Cyclic oral administration of melphalan (0.15-0.25 mg / kg of body weight per day) and prednisolone (1.5-2.0 mg / kg per day) for four to seven days every four to six weeks during the year, until a course dose of 600 mg is reached.
- Oral use of melphalan at a dose of 4 mg / day for three weeks, then, after a two-week break - 2-4 mg / day four days a week continuously, until a course dose of 600 mg is reached, in combination with prednisolone.
- Intravenous administration of high doses of melfolan (100-200 mg/m2 of body surface for two days) followed by transplantation of autologous stem cells.
- Intravenous administration of dexamethasone at a dose of 40 mg for four days every three weeks - eight cycles.
- Intravenous administration of dexamethasone at a dose of 40 mg on days 1-4, 9-12 and 17-20 of a 35-day cycle, three to six cycles, followed by oc-interferon at a dose of 3-6 million units three times in Week.
- Vincristine-doxoribucin-dexamethasone (VAD) scheme.

The development of chronic renal failure is an indication for planned dialysis.
Peritoneal dialysis is preferred, as it creates conditions for the removal of b2-microglobulin.
Survival of patients with amyloidosis of the kidneys on hemodialysis is lower than in patients with other causes of CRF (one-year survival rate of 60%).

Kidney transplantation is performed for AA amyloidosis (subject to successful treatment of the underlying disease) and AL amyloidosis.
However, survival rates are lower than for other renal pathologies, which is associated with severe extrarenal organ damage, mainly cardiovascular.

Recurrence of amyloidosis in the graft is common but has little effect on the overall prognosis.
By liver transplantation, the place of synthesis of the amyloid precursor, transthyretin, is eliminated.
Splenectomy is performed in order to stop the hemorrhagic syndrome (elimination of the spleen, which binds the largest amount of factor X).
"Miracles" in recent years are associated with the use of stem cells. Let's dream together. Employees of the Pittsburgh Institute of Malignant Tumors proposed the following technique.
First, Neupogen is administered intravenously for 4 days, which stimulates the release of hematopoietic stem cells into the peripheral bloodstream. Then, using special equipment, a fraction of stem hematopoietic cells is isolated from the blood.
After that, the isolated cells are frozen in a cryochamber so that they can be stored for a long time.
After preparing the "medicine", the patient is given a course of high-dose chemotherapy for one or two days to destroy the proteins in the blood plasma.

After the course of chemotherapy, the patient is injected intravenously with his own stem cells, which were frozen.

Forecast.
The cause of death was heart or kidney failure.
After the development of CRF, patients usually live less than a year, after the development of HF - about 4 months.
In secondary amyloidosis, the prognosis is better than in AL-amyloidosis.
In any type, the disease is more severe in the elderly.