Glymphatic System Pathology and Neuroinflammation as Two Risk Factors of Neurodegeneration.

The key to the effective treatment of neurodegenerative disorders is a thorough understanding of their pathomechanism. Neurodegeneration and neuroinflammation are mutually propelling brain processes. An impairment of glymphatic system function in neurodegeneration contributes to the progression of pathological processes. The question arises as to how neuroinflammation and the glymphatic system are related. This review highlights the direct and indirect influence of these two seemingly independent processes. Protein aggregates, a characteristic feature of neurodegeneration, are correlated with glymphatic clearance and neuroinflammation. Glial cells cannot be overlooked when considering the neuroinflammatory processes. Astrocytes are essential for the effective functioning of the glymphatic system and play a crucial role in the inflammatory responses in the central nervous system. It is imperative to acknowledge the significance of AQP4, a protein that exhibits a high degree of polarization in astrocytes and is crucial for the functioning of the glymphatic system. AQP4 influences inflammatory processes that have not yet been clearly delineated. Another interesting issue is the gut-brain axis and microbiome, which potentially impact the discussed processes. A discussion of the correlation between the functioning of the glymphatic system and neuroinflammation may contribute to exploring the pathomechanism of neurodegeneration.

Glymphatic System and Mitochondrial Dysfunction as Two Crucial Players in Pathophysiology of Neurodegenerative Disorders.

Neurodegenerative diseases are a complex problem affecting millions of people around the world. The pathogenesis is not fully understood, but it is known that both insufficiency of the glymphatic system and mitochondrial disorders affect the development of pathology. It appears that these are not just two independent factors that coexist in the processes of neurodegeneration, but that they often interact and drive each other. Bioenergetics disturbances are potentially associated with the accumulation of protein aggregates and impaired glymphatic clearance. Furthermore, sleep disorders characteristic of neurodegeneration may impair the work of both the glymphatic system and the activity of mitochondria. Melatonin may be one of the elements linking sleep disorders with the function of these systems. Moreover, noteworthy in this context is the process of neuroinflammation inextricably linked to mitochondria and its impact not only on neurons, but also on glia cells involved in glymphatic clearance. This review only presents possible direct and indirect connections between the glymphatic system and mitochondria in the process of neurodegeneration. Clarifying the connection between these two areas in relation to neurodegeneration could lead to the development of new multidirectional therapies, which, due to the complexity of pathogenesis, seems to be worth considering.