Interaction Between the Glymphatic System and α-Synuclein in Parkinson’s Disease

Correlation of glymphatic system abnormalities with Parkinson's disease progression: a clinical study based on non-invasive fMRI.

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 Pathology and Neuroinflammation as Two Risk Factors of Neurodegeneration

The term "glymphatic" emerged roughly a decade ago, marking a pivotal point in neuroscience research. The glymphatic system, a glial-dependent perivascular network distributed throughout the brain, has since become a focal point of investigation. There is increasing evidence suggesting that impairment of the glymphatic system appears to be a common feature of neurodegenerative disorders, and this impairment exacerbates as disease progression. Nevertheless, the common factors contributing to glymphatic system dysfunction across most neurodegenerative disorders remain unclear. Inflammation, however, is suspected to play a pivotal role. Dysfunction of the glymphatic system can lead to a significant accumulation of protein and waste products, which can trigger inflammation. The interaction between the glymphatic system and inflammation appears to be cyclical and potentially synergistic. Yet, current research is limited, and there is a lack of comprehensive models explaining this association. In this perspective review, we propose a novel model suggesting that inflammation, impaired glymphatic function, and neurodegenerative disorders interconnected in a vicious cycle. By presenting experimental evidence from the existing literature, we aim to demonstrate that: (1) inflammation aggravates glymphatic system dysfunction, (2) the impaired glymphatic system exacerbated neurodegenerative disorders progression, (3) neurodegenerative disorders progression promotes inflammation. Finally, the implication of proposed model is discussed. 

The relationship between inflammation, impaired glymphatic system, and neurodegenerative disorders: A vicious cycle

Astrocytes are one of the key glial types of the central nervous system (CNS), accounting for over 20% of total glial cells in the brain. Extensive evidence has established their indispensable functions in the maintenance of CNS homeostasis, as well as their broad involvement in neurological conditions. In particular, astrocytes can participate in various neuroinflammatory processes, e.g., releasing a repertoire of cytokines and chemokines or specific neurotrophic factors, which result in both beneficial and detrimental effects. It has become increasingly clear that such astrocyte-mediated neuroinflammation, together with its complex crosstalk with other glial cells or immune cells, designates neuronal survival and the functional integrity of neurocircuits, thus critically contributing to disease onset and progression. In this review, we focus on the current knowledge of the neuroinflammatory responses of astrocytes, summarizing their common features in neurological conditions. Moreover, we highlight several vital questions for future research that promise novel insights into diagnostic or therapeutic strategies against those debilitating CNS diseases. 

Astrocyte-Mediated Neuroinflammation in Neurological Conditions

Accumulating evidence indicates that the glymphatic system has a critical role in maintaining brain homeostasis. However, the detailed anatomy of the glymphatic pathway is not well understood, mostly due to a lack of high spatial resolution 3D visualization. In this study, a fluorescence micro-optical sectioning tomography (fMOST) was used to characterize the glymphatic architecture in the mouse brain. At 30 and 120 min after intracisternal infusion with fluorescent dextran (Dex-3), lectin was injected to stain the cerebral vasculature. Using fMOST, a high-resolution 3D dataset of the brain-wide distribution of Dex-3 was acquired. Combined with fluorescence microscopy and microplate array, the heterogeneous glymphatic flow and the preferential irrigated regions were identified. These cerebral regions containing large-caliber penetrating arteries and/or adjacent to the subarachnoid space had more robust CSF flow compared to other regions. Moreover, the major glymphatic vessels for CSF influx and fluid efflux in the entire brain were shown in 3D. This study demonstrates the regional heterogeneity in the glymphatic system and provides an anatomical resource for further investigation of the glymphatic function.

High-resolution 3D demonstration of regional heterogeneity in the glymphatic system

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Interaction Between the Glymphatic System and α-Synuclein in Parkinson’s Disease

High-resolution 3D demonstration of regional heterogeneity in the glymphatic system