Insights into solute trafficking via the meningeal lymphatic system Public Deposited

Historically, the complex anatomical landscape of the central nervous system and the physiology that governs it presented a challenge for scientists interested in elucidating fundamental properties of solute trafficking in the central nervous system. This resulted in a wide range of conflicting models of fundamental physiological processes, such as the production and reabsorption of cerebrospinal fluid in the cranium. Major advances were recently made in the study of solute trafficking between the brain and cerebrospinal fluid, and the reabsorption of cerebrospinal fluid and solutes therein. These findings challenge the previous assumptions about where cerebrospinal fluid (CSF) circulates through the cranium and how it is reabsorbed. One such finding is the characterization of differentiated lymphatic vessels in the dura mater of the mouse. Discovered independently by two different groups, this revealed a new potential pathway for the efflux of macromolecules, cells, and fluid out of the central nervous system. Although interest in this putative pathway between the intracranial space and deep cervical lymph nodes (DCLNs) was invigorated by these findings, several important gaps in our current knowledge exist. First and foremost is the translational relevance of this finding to human anatomy. Although robust characterizations were carried out in the rodent, it remains unclear if the human meninges contain analogous lymphatic structures. Second, since the discovery of a lymphatic network in the meninges, there was widespread speculation that it plays a role in the development of neurological disease, particularly in Alzheimer’s dementia. While this is possible, foundational studies examining the trafficking of amyloid beta along this pathway do not yet exist. Third, there is a paucity of data in the literature concerning the physiological parameters that mediate the lymphatic absorption of solutes in the brain and cerebrospinal fluid. The work described in this dissertation aims to address these knowledge gaps using a combination of light microscopy, transgenic animal models, and experimental manipulation of physiological parameters that act on this biological system.

  • 0000-0001-9486-9898
  • 10.6083/qn59q458n
  • goodman.james.2019.pdf
  • 2019
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