The Interplay between Meningeal Lymphatic Vessels and Neuroinflammation in Neurodegenerative Diseases

Abstract

Meningeal lymphatic vessels (MLVs) are essential for the drainage of cerebrospinal fluid, macromolecules, and immune cells in the central nervous system. They play critical roles in modulating neuroinflammation in neurodegenerative diseases. Dysfunctional MLVs have been demonstrated to increase neuroinflammation by horizontally blocking the drainage of neurotoxic proteins to the peripheral lymph nodes. Conversely, MLVs protect against neuroinflammation by preventing immune cells from becoming fully encephalitogenic. Furthermore, evidence suggests that neuroinflammation affects the structure and function of MLVs, causing vascular anomalies and angiogenesis. Although this field is still in its infancy, the strong link between MLVs and neuroinflammation has emerged as a potential target for slowing the progression of neurodegenerative diseases. This review provides a brief history of the discovery of MLVs, introduces in vivo and in vitro MLV models, highlights the molecular mechanisms through which MLVs contribute to and protect against neuroinflammation, and discusses the potential impact of neuroinflammation on MLVs, focusing on recent progress in neurodegenerative diseases.

Promising Strategies to Reduce the SARS-CoV-2 Amyloid Deposition in the Brain and Prevent COVID-19-Exacerbated Dementia and Alzheimer’s Disease

“…Because MLVs play an important role in draining brain tissues and removing toxins and metabolites from the brain, future treatments for reversible forms of dementia are expected to involve stimulation of lymphatic drainage processes. Given the growing evidence of the existence of lymphatic vessels directly in the human brain [ 292 , 293 , 294 , 295 ], and not only in its meninges [ 296 , 297 ], technologies for activating lymphatic drainage processes will contribute to progress in the treatment of a wide number of brain diseases associated with dysfunction of the cerebral lymphatic system, such as AD, Parkinson’s disease, brain trauma and oncology [ 44 , 45 , 46 , 47 , 48 , 49 , 118 , 119 , 162 , 275 , 276 ].…”

“…These data indicate that MLVs facilitate lymphatic clearance of viruses, suggesting a promising MLV-based therapeutic approach against neurotropic viral infection [ 114 ]. Since MLVs play an important role in eliminating toxins and wastes from the brain, it is assumed that augmentation of MLV function could be a promising therapeutic target for preventing or delaying age-associated neurocognitive diseases, including COVID-19-mediated AD dementia [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 128 , 129 ].…”

“…The mechanisms of PBM-mediated improvement of cognitive function in healthy subjects and with AD are not clear, but it is most likely that it may be due to PBM stimulation of MLV function. Indeed, disruption of MLVs aggravates AD, leading to cognitive deficit and behavioral alterations [ 44 , 47 , 48 , 49 , 50 , 160 , 161 ]. Thus, MLV dysfunction might cause cognitive decline and neurodegenerative disease due to aggregation of toxins in the brain, while PBM-stimulation of their lymphatic removal can improve the brain homeostasis, immunity and neuroprotection [ 43 , 44 , 46 , 47 , 48 , 49 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 ].…”

“…Indeed, disruption of MLVs aggravates AD, leading to cognitive deficit and behavioral alterations [44,[47][48][49][50]160,161]. Thus, MLV dysfunction might cause cognitive decline and neurodegenerative disease due to aggregation of toxins in the brain, while PBM-stimulation of their lymphatic removal can improve the brain homeostasis, immunity and neuroprotection [43,44,[46][47][48][49].…”

“…However, Aβ immunotherapy can be improved by modulation of functions of the meningeal lymphatic vessels (MLVs) [43]. MLVs are now thought to be the major route for clearance of amyloids in AD [44][45][46][47][48][49]. Therefore, strategies for augmentation of lymphatic removal of amyloids from the brain can lay the foundation for the development of promising therapeutic approaches for AD [44].…”