Researchers tend to pay more and more attention to inflammatory processes in the brain in degenerative diseases, both in the role of the root cause and in the role of the secondary factor caused by damage to the nervous tissue. Neuro-inflammation may be the central process in the aging of the body.

    It is very difficult to determine neuroinflammation in the context of neurodegenerative diseases, although, for example, in multiple sclerosis (an autoimmune disease that has nothing to do with household sclerosis), this is not a problem. In the latter case, the lymphocytes and monocytes in excess penetrate the barrier separating the nervous tissue from the bloodstream, causing impaired function.

    With pathologies that include Alzheimer's disease, which you probably know from the state of the writer Terry Pratchett before his death, Parkinson's disease, from which the artist Salvador Dali suffered in the last years of his life, amyotrophic lateral sclerosis, which became known due to the state of physicist Steven Hawking, the description is based on the reaction, expressed in changing the shape and structure of glial cells - astrocytes and microglia. Many of these diseases manifest themselves in older age, they are associated with aging and possibly caused by them. Understanding of neuroinflammation, its causes and consequences, can potentially improve the treatment of many diseases, some of which are now treated only symptomatically.

    In order to understand the phenomenon of neuro-inflammation, it is first necessary to understand what inflammation is. The proposed issue is more than 2000 years old, but the definition of inflammation, which would lead scientists and doctors all over the world to a consensus, has not yet been proposed.

    What is inflammation?

    "Rubor, et tumor, cum calore et dolore." Redness, swelling with heat and pain - this is how the ancient Roman physician Cornelius Celsus describes inflammation. This definition lacks important details that his colleague, surgeon Galen, specifies, about 100 years after his predecessor - functio laesa or dysfunction.

    In the aggregate, these five described symptoms briefly convey the whole essence of the manifestations of inflammation, and in almost unchanged form reach to our days. Medical students are still the first thing to remember a Latin patter when answering the exam.

    But we are absolutely not satisfied with such a definition, since it says nothing about the mechanisms of the development of pathology and its etiology. The physiologists had to tinker with the disclosure of the details of the latter. History remembers many theories that primarily concerned the role of blood vessels in the development of inflammation, but a more significant understanding emerged after Ilya Mechnikov paid attention to the cells and derived his definition:

    “In general, inflammation should be considered as a phagocytic reaction of the body against annoying personalities; this reaction is performed by mobile phagocytes alone, then by the action of vascular phagocytes or the nervous system. ”

    Phagocytes, cells capable of absorbing and destroying harmful foreign particles, were the central focus of Mechnikov's work. Accordingly, the main reason for criticizing its definition was the lack of recognition of the role of proteins dissolved in body fluids, which, as is now known, have a significant influence on the process. We are impressed by this definition due to the mention of the nervous system, let the Mechnikov add it only to recognize the nervous regulation of the vascular wall, which also modulates the course of inflammation.

    With the definition for neurospine, things are really bad. If you open Wikipedia, you can find out that "neuroinflammation is an inflammation of the nervous tissue." Here is such a circulus in definiendo, a logical error in which the statement is derived from itself.


    An interesting definition can be found in the ACS chemical neuroscience editorial column, which defines neuroinflammation as non-autonomous cell processes that cause cell death, dysfunction or recovery of neurons and oligodendrocytes during a neurodegenerative disease.

    "CNS cell death, dysfunction or neurons and oligodendrocytes during the course of neurodegenerative disease."


    This is a very good definition, which describes the bad and good sides of neuroinflammation, however it limits this process to the scope of a neurodegenerative disease. What happens, before a person has not noticed Alzheimer's or Parkinson's, cannot he have inflammation in his brain?

    Behind this the question of definition remains open. Consider the facts and interpretation of research in this area.

    Why do I need inflammation?

    If there were no regeneration, life would be impossible.
    If everything regenerated, death would be impossible.
    “If there were no regeneration, there could be no life.
    If everything regenerated there would be no death. ”
    - Richard Goss

    What is the essence of inflammation? Friend or foe? - friend or foe? - as international scientific publications and popular science portals write in their desire to convey to the reader the entire complexity of the processes of the phenomenon being described.

    The main objective of such a process as inflammation is to inform the body of the existing damage or breakdown. And the body is already "must make a decision and act accordingly." Most often, this decision is made by a cooperative from local and systemic immune cells, which first remove the damaging factor, and then work together to restore the homeostasis of the affected tissue, as far as they succeed.

    Events take such a turn, for example, with traumatic damage to nervous tissue. In the first moments after an unfortunate set of circumstances or a planned laboratory action in vertebrates, there is a massive death of cells affected by injury.

    The first wave of cell death due to necrosis and apoptosis (a programmed cell suicide that received injuries incompatible with life) subsides after a few hours, after which it is followed by a longer second wave, probably caused by the effect of degradation products on the surrounding tissues. In this case, the interaction between the nervous tissue and the vascular tissue may be disturbed, as a result of which interruptions in the supply of energy, ions and necessary substances occur.

    Activation of microglia in response to damage occurs immediately. Microglial cells, these tiny macrophages, directly perform the “phagocytic reaction of the body against irritating agents,” as Mechnikov describes.

    Schematic representation of astrocyte and neuron near the blood vessel.

    They constantly probe the surrounding space for substances that may indicate damage to the neurons or threaten their integrity. In the absence of such danger signals, the activity of macrophages in the nervous tissue is inhibited by peptides secreted by neurons, which are not at risk. Otherwise, when an injury occurs, the microglia is activated in minutes! This is reflected in their form and function. Cells become more mobile, can begin division, bring numerous receptors to the outer membrane for a more accurate assessment of the situation. When activated, they throw the proteins of the complement system and chemokines into the extracellular space, which attract a greater number of immune cells to the injury site, cytokines, which force the neighbors to react to the situation,


    Astrocytes do not lag behind their glial counterparts. Being represented by the most numerous class of cells in the central nervous system, they occupy a strategic position between vascular endothelial cells and neurons, regulating the work of the barrier between the blood and the brain. After injury, they react either to danger signals that originate from neurons, or to substances secreted by activated microglia. Then astrocytes increase in size, hypertrophying, releasing neuroregulatory peptides, for example, BDNF (brain-derived neurotrophic factor) or neurotrophic factor of the brain, which contributes to the survival of damaged neurons. They also produce and secrete fibrillar proteins that regenerate the extracellular matrix and form a glial scar. On the one hand, this is a good thing,

    Migration of leukocytes to the site of damage

    Microglia and astrocytes play foreground roles in traumatic damage; nevertheless, this scenario has extensive extras. In the shortest time after injury to the scene, leukocytes literally roll in (this is their normal form of movement through the endothelium during inflammation). Of the entire host of leukocytes, neutrophils arrive first, which begin to actively secrete pro-inflammatory cytokines, reactive oxygen species and peptides, which induce cells to apoptosis. Their stay in the place of injury is temporary, after 48 hours they are no longer observed, however their appearance is one of the most important early events.

    Behind them, microglia are activated, T and B lymphocytes are recruited, which respond to protein changes caused by damage. In the early stages, red blood cells and platelets sometimes also get damaged. They are also very actively involved in the regulation of neuro-inflammation, although this happens only when the vascular wall is damaged. These cells produce platelet activating factor, which is involved in the regulation of microglial activation, and besides that which may sound unexpected, they are an additional source of serotonin (it is produced not only within the nervous system, but also far beyond). Serotonin in this case helps to stop the outflow of blood from the vessels, the survival of neurons and the preservation of their plasticity.

    Nerve cells are not restored?

    As Santiago Ramon y Kahal postulated, the founder of modern neuroscience, at the beginning of the 20th century, nerve cells in an adult organism are not restored. You must have heard this statement more than once in the form of the phrase "lost nerves are not restored." However, in the 60s of the last century, Joseph Altman announced the discovery of the division of neurons in the hippocampi of mature guinea pigs.


    These evidences of adult neurogenesis were not taken seriously until the 1990s. The accumulated data on the neurogenesis of various species, including primates, has led to a paradigm shift.


    Researchers confirmed that neurogenesis actually occurs in the brain of various adult animals, and eventually found traces of newly formed neurons in the adult brain. It is assumed that hundreds of such cells are produced every day in the hippocampus, where they help shape memory and new skills. This concept is widely accepted by scientists, and you can even find diets and special exercises that supposedly enhance it. Predictably, you can even find TED talk about this phenomenon.

    That's just the problem: this update neurons may actually not be. Studies that disprove the existence of adult neurogenesis continue to appear until today. The last such large study was published on March 15 of this year in the journal Nature. In it, scientists from the California Institute of San Francisco conclude that they could not find any traces in a few dozen hippocampi, derived from the brains of adults who bequeathed their bodies to science. According to the researchers, they did not find any signs even in the best-preserved specimens.


    As usual, it is very difficult to prove that something is really not there, and many scientists are skeptical about the results of their work. Many indicate that the calculation was carried out indirectly - by the presence of proteins, which are usually produced by young, recently divided cells. These proteins could easily degrade shortly after the death of the organism.

    It is very likely that the debate will continue further, and the last word on this issue will be put only when techniques for observing neurons in the brain of living people are developed.

    In the brain of zebrafish, the neurons of the lateral wall of the ventricles are able to divide, and then move into the affected area, forming young neurons to replace the dead. The corresponding cells of the mice that are closer to us are no longer capable of such a focus, although being placed in a test tube in vitro, the ability is restored. It is believed that the microenvironment in the place of injury in such highly developed animals hinders the development of new neurons.


    When tissue is damaged, the microenvironment is formed by the breakdown products of proteins and other macromolecules of which it consists, as well as of substances secreted by the surrounding cells. The specific actions of glial cells and their role in the recovery strongly depend on the nature of the injury. When microglia are excessively and continuously activated, the substances secreted by it in high concentrations become toxic to the surrounding cells, the produced cytokines disrupt the functioning of neurons; fibrillar proteins secreted by astrocytes inhibit the formation of functional bonds.

    A high amount of interleukin 1, one of the major mediators of inflammation, especially its beta form, together with the tumor necrosis factor, interleukins 6 and 10, produced in the central nervous system in case of damage, can lead to headaches and migraines.

    It should be remembered that these pro-inflammatory cytokines are necessary for the restoration of the affected tissue, despite the fact that they in turn can cause cell death and cause secondary damage to the tissue. For example, tumor necrosis factor alpha is toxic to neurons in the initial stages of inflammation, but it promotes regeneration in the later stages.

    Neurospiolitis in Alzheimer's disease

    As evident from the definition given above, neuroinflammation is a frequent companion of neurodegenerative diseases. Such diseases are characterized by loss of structure, function and number of neurons.

    The disease, first described by the German psychiatrist Alois Alzheimer, usually affects people over 65, although other forms are sometimes found. With the development of the disease, patients lose the ability to remember information, and in extreme cases lose their long-term memory, ability to speak, orient themselves in the setting and look after themselves. The cause of many cognitive impairments in this pathology is the degeneration of neurons and synapses, leading to atrophy of the cerebral cortex.

    Microglia in the role of one of the main participants in neuroinflammation becomes active after exposure to one of the many stimuli, namely hypoxia, trauma, stroke, along with such factors as viruses, bacteria and toxins. Also, cells are activated when amyloid plaques and accumulations of tau proteins appear. It is these two factors — neurofibrillary tau tang protein and neuroinflammation — that are key signs of Alzheimer's disease.


    Activated microglia is observed in excess in the patient's brain when examined by a post-mortem pathologist. Apparently, in the presence of pro-inflammatory cytokines, macrophages of the brain lose the ability to phagocytose extracellular accumulations of beta-amyloid, a group of peptides forming a characteristic plaque. In addition, an increased concentration of cytokines, such as interleukin 1 beta, prevents the formation of synapses, which explains their loss in the pathological process.

    Neurospiolitis in Alzheimer's disease

    Given the enormous damage inflicted on the brain by chronic inflammation, it has been suggested that inflammatory substances can cure the disease or at least reduce the likelihood of its development. There is evidence that nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, can reduce the inflammation caused by amyloid plaques, but clinical trials have not been completed due to the high risk of side effects. Currently, NSAIDs are not considered useful in the treatment of Alzheimer's disease, and none of the clinical trials to prove the ability of NSAIDs to prevent or reduce the risk of developing the disease has not been completed.

    The results of recent studies in general cast doubt on the benefits of taking daily low doses of aspirin and potentially other NSAIDs. The study, published in one of the most influential medical peer-reviewed scientific journals Lancet, where doctors and scientists monitored more than 12,000 patients with a moderate risk of developing heart disease, did not confirm any benefit in taking this medication.


    Neurospiolitis in Parkinson's Disease

    But what about the other neurodegenerative diseases? In Parkinson's disease, characterized by the massive death of neurons in the basal ganglia secreting dopamine, neuroinflammation is almost the main component of the disease.

    People with Parkinson lose control of their movements, their hands begin to shake, their handwriting worsens. Patients begin to walk more slowly, they have problems with walking. These are all early manifestations of the disease. Over time, abstract thinking and attention control worsens and hallucinations appear. The latter have almost 50% of those diagnosed.

    Early post mortem brain tests reveal the entire repertoire of proinflammatory cytokines, including interleukins 1, 2, 6, interferon gamma, tumor necrosis factor alpha, and others. The same set is observed in the cerebrospinal fluid of patients. High concentrations of nitric oxide and superoxide, which can directly and indirectly cause neuronal death, are also detected.


    However, despite the great success in studying the presented pathology, researchers find it difficult to say for sure whether neuroinflammation is the cause or consequence of the disease. One thing is certain: as soon as inflammation is drawn into the game, it becomes a key player. This is confirmed by epidemiological studies. Unlike Alzheimer's disease, NSAIDs, with the exception of aspirin, can reduce the risk of developing Parkinson's disease according to a meta-analysis conducted in 2010.


    A characteristic feature of many neurodegenerative diseases is that their risk of development increases with age. From this we can assume that neuroinflammation and aging are also somehow connected.

    Neuroinflammation during aging

    Brain cells live and die, this is the normal life cycle. Neurons are gradually replaced by astrocytes, and cytokines released at their death control inflammation and recovery. Thus, at any given point in time, a certain level of pro-inflammatory cytokines is present in the brain. However, with age, the markers of inflammation in glia become larger, and in addition, they contribute to an excessive immune response during stimulation. Microglia becomes hyperactive.

    With aging, there are also disorders of cognitive functions — memory, speech, and abstract thinking — albeit to a lesser extent than with neurodegenerative diseases. In general, aging can be considered the main risk of mild cognitive disorders.

    Older people often show signs of cognitive impairment during or after infection or stress. These observations are confirmed in laboratory experiments on mice, whose cognitive disorders can be caused by administering lipopolysaccharide (a component of the bacterial wall to which the immune response is developing), but which can be reduced using resveratrol, a strong anti-inflammatory agent.


    Hippocampus aging

    Any description of aging of the central nervous system invariably begins with the hippocampus, the brain region responsible for the formation of memories. It is affected by both normal aging and Alzheimer's disease. In addition to memory, the hippocampus intrigues researchers with the effects of stress. Since the hippocampus is an important feedback element responsible for stopping the production of glucocorticoids, the effect of chronic stress on aging is under scrutiny.

    In early studies on the aging of the hippocampus, it was shown that the elderly have a significant loss in the number of neurons. However, in later studies using exact techniques, physiologists found minimal differences between the number of neurons in the hippocampi of young and old people.

    A very similar situation exists with the volume of the hippocampus, as measured using magnetic resonance imaging. It is authentically known that the smaller the volume of the hippocampus, the worse the memory of an elderly person will be. Fortunately, there are studies that show that moderate aerobic workouts help preserve the volume of the hippocampus.

    Effects of cortisol on the brain during stress

    Because the hippocampal neurons have a significant amount of glucocorticoid receptors, they are vulnerable to long-term stress. In people who suffer from severe and long-term traumatic stress, the hippocampus atrophies faster than the rest of the brain.

    Similar effects are observed in post-traumatic stress disorder, schizophrenia and depression. Interestingly, atrophy in depression can be slowed by taking antidepressants even if they do not help to cope with other symptoms.

    Neuroinflammation in mental disorders

    In general, an interesting picture is formed around depression. The reasons for it are still unknown; The most popular serotonin theory is constantly criticized. At the same time, patients with chronic inflammation often show signs and symptoms of depression. This year, a paper was published, where scientists determined that psychological stress, including social factors, increases the level of inflammation in the brain of mice. Mice periodically met with an aggressive male for 10 days. Such stress caused an increase in the amount of interleukin 1 and tumor necrosis factor secreted by activated microglia in the prefrontal cortex, a region of the brain that is responsible for making decisions. Such a violation eventually led to episodes of severe depression, which was cured by neutralizing inflammation.

    Sleep disturbance, described in experimental conditions, causes activation of the same innate immunity receptors as social stress.


    Due to the fact that neuroinflammation can play a key role in psychiatric diseases - depression, schizophrenia, bipolar disorder - this phenomenon becomes extremely curious, since the results of these experiments imply the conclusion that these diseases can be prevented long before their appearance by correcting lifestyle , diet and sleep patterns.


    Aging of the hypothalamus

    Unlike the hippocampus, whose changes explain the occurrence of cognitive impairment with age, the hypothalamus probably controls aging.

    This structure in the brain, similar to the tonsil, is a bridge between the nervous and endocrine systems of the human body. It helps regulate behavior and many basic needs, such as hunger, sleep, fear, and aggression. Accordingly, the homeostasis of secreting nerve cells that make up the hypothalamus is disturbed with age, and manifestations associated with aging manifest.

    The first searches in this direction concerned the establishment of feedback chains of various hormones, often sex hormones. However, feedback disorders and the emergence of resistance to estrogen, insulin, growth hormone and other regulatory molecules are a consequence, not a cause. The cellular and molecular mechanisms explaining the loss of homeostasis have not yet been studied thoroughly.

    Over the past few years, several molecular paths and genes associated with the onset and progression of age-dependent degenerative processes have been considered. Among them were now very popular among researchers sirtuins, SIRT, mammalian target mammalian rapamycin protein, mTOR, transcription factor NF-kB, and others.

    mTOR is an enzyme belonging to the family of protein kinases, which is the target of the anticancer drug rapamycin. As a result of research on yeasts, worms, flies and some mammals, rapamycin has been shown to prolong the life of these model organisms. So mTOR has earned a reputation as the central, evolutionarily conservative determinant of life expectancy.

    mTOR is very sensitive to insulin and growth factors; it controls the metabolism of the cell, its growth and survival. However, in chronic high stimulation, excessive work of mTOR leads to oxidative stress, accumulation of damage and cell aging — all signs of the inflammatory response of the cell.

    Activation of the transcription factor NF-kB contributes to the further development of the inflammatory response, since it controls the genes responsible for maintaining it. In a recent research paper, it has been shown that a constant excess of calories in food can contribute to the development of inflammatory responses in the hypothalamus.

    Neurospine with excess nutrition

    Excess nutrients have a domino effect. First of all, it suffers from endoplasmic reticulum - an extensive network of cavities, vesicles and tubules, associated with a large number of metabolic functions: transport of proteins and lipids, accumulation of calcium, and so on. When this important organoid experiences stress in the hypothalamic microglia, NF-kB is activated in these cells. Microglial cells are in continuous communication with neurons through pro-inflammatory cytokines, such as tumor necrosis factor alpha and interleukin 1 beta.

    Increasing their expression activates NF-kB in secreting neurons, suppressing the production of GnRH, a hormone that controls the production of pituitary gonadotropic hormones, and promoting insulin and leptin resistance.

    Over time, this weakly shatters hypothalamic homeostasis. This dysregulation is associated with systemic aging and the development of age-related pathologies - diabetes, obesity, cardiovascular diseases, dementias, and reproductive dysfunction.
    www.ncbi.nlm.nih .gov / pmc / articles / PMC4313775

    Stem cells and neuroinflammation

    In 2013, researchers from the Albert Einstein College of Medicine discovered hypothalamus stem cells, which in their opinion are also able to control the aging of the body. They report that the number of stem cells in the hypothalamus decreases over time in mice that have been the subject of research. By the age of two - the age of old mice - most of these cells do not remain with them.

    The experimenters transplanted stem cells to normal mice, as well as mice, to which they had previously destroyed the hypothalamic stem cells. Both groups showed signs of delayed aging. It turned out that specific miRNAs were the key effector in this phenomenon. This group of molecules differs from ordinary RNAs in that they are not involved in the process of protein synthesis, but instead are involved in regulating the expression of other genes in cells. A cell can secrete miRNAs in special containers - exosomes.

    To confirm their hypothesis, experimenters isolated the exosomes of hypothalamic stem cells and injected spinal fluid into normal mice and mice that had their hypothalamus stem cells destroyed. The result exceeded all expectations: again, both groups of mice grew older more slowly - their muscle strength, motor coordination, social behavior, and cognitive abilities were evaluated.


    Although several microRNAs are already known that play an important role in inflammation, such as miR-107, miR-155 and miR-223, it was not studied in this work which microRNA was responsible for slowing down aging.

    Research miRNAs are still only at the beginning, and insights on how they can be used to increase the duration of healthy life may be waiting for us in the near future.


    As you can see, neuro-inflammation is an extremely complex process. When it is not observed classical manifestations of inflammation, described by Celsus, namely redness, swelling with fever and pain. However, during neuroinflammation, the molecular and cellular mechanisms are partially the same as in inflammation. In either case, signaling molecules or cytokines, such as interleukins, chemokines, and tumor necrosis factor, are involved. Both processes have positive and negative sides.

    The key to these processes is the body's attempt to repair damaged tissue in the ways that are available to it. There are differences. Microglial cells are the resident macrophages in the brain tissue. They are not found in other tissues of the body. Instead of the usual scar in the nervous tissue, glial tissue is formed due to the activation of astrocytes.

    Not surprisingly, inflammation in the nervous tissue, especially the central nervous system, has far-reaching consequences. Neuro-inflammation is involved in aging, age-related pathologies, obesity, and certain types of dementia.

    Despite the fact that much in health depends on genetics, our behavior also partly determines how we will live and grow old. Moderate exercise and, again, a moderate, healthy and varied diet, healthy sleep can reduce neuro-inflammation, as well as prolong the health of the brain and body. It is also necessary to seek the help of doctors in time, even if it is “some kind of depression” and will pass by itself. And also you should not take a great interest in self-treatment, and guessing about pubs, which came into our society to replace the diagnosis of google.

    Author Vasily Tsvetkov

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