Inflammation in the pathogenesis of neurodegenerative diseases

Abstract

Summary
 Introduction. Neurodegenerative diseases (ND) are common chronic disorders associated with progressive damage to the nervous tissue system. The participation of the immune system in the development of neurodegenerative diseases was confirmed by data on the activation of microglia, the presence of an imbalance in the composition and phenotype of peripheral immune cells and the presence of disorders of humoral immunity, dysbiosis of the intestinal microbiota in patients with this pathology.
 Discussion. It has been established that inflammation plays a key role in the pathogenesis of diseases associated with progressive damage to the nervous system. The article analyzes the mechanisms of development of “subclinical” chronic inflammation that leads to the development of old age and related diseases, including neurodegenerative pathology. At least three groups of factors associated with old age play a role in the formation of a “proinflammatory status”: mitochondrial dysfunction, the development of an age-related “proinflammatory” status of the immune system, and chronic stress. Mitochondrial dysfunction is associated primarily with disruption of mitophagy processes: failure of quality control mechanisms as a result of disruption of mitophagy processes leads to the accumulation of terminally damaged mitochondria, which become a threat to cell survival. Inadequate removal of damaged mitochondria leads to hyperactivation of inflammatory signaling pathways and subsequently to chronic systemic inflammation and the development of inflammatory diseases. A high level of deletions in the mitochondrial genetic apparatus that accumulates with age inevitably leads to increased formation of reactive oxygen species, which in turn are assumed to be one of the leading activators of the cytosolic NLRP3 protein, the main component of inflammasomes. Increased inflammosome formation ultimately leads to caspase-1-dependent production of proinflammatory interleukins. Age-related inflammatory imbalance is associated with the fact that during life the immune system, the main protective mechanism of which is the inflammatory response, copes with constant antigenic attacks. However, over time, upon reaching a certain threshold, the reaction of the immune system becomes excessive, characterized by increased production of coagulation factors, proinflammatory cytokines, acute phase proteins of inflammation, prostaglandins and leukotrienes.
 Conclusion. Immunological changes that develop during chronic (long-term) stress are the result of a disruption of the homeostatic connection between the neuroendocrine and immune systems, leading to the formation of an inflammatory background that complements the “pro-inflammatory status” that develops as a result of age-related changes in the immune system and disruption of mitophagy mechanisms.