The Role of Tissue Stiffening on Meningeal Lymphatic Function
Year: 2024
Type: dissertation
Abstract: Aging is a significant risk factor for the development of neurological disorders, including Alzheimer’s disease and Parkinson’s disease, which are characterised by abnormal protein accumulation in the central nervous system (CNS). A failure to effectively clear these CNS waste proteins is believed be a key contributor to the pathophysiology of these diseases. Recent attention has focused towards the meningeal lymphatic system and glymphatic system for their roles in CNS waste removal. The function of both systems are significantly perturbed with aging, leading to impaired CNS waste clearance; however, the mechanisms underlying this deficit remain elusive. This project investigates how age-related factors in the meninges— particularly T cell responses—contribute to tissue fibrosis in the dura mater and describe the impact of this on meningeal lymphatic and glymphatic function. Excessive extracellular matrix deposition, particularly around dural sinuses, is observed in aging, yet the cause and consequences of this remain unclear. To investigate fibrosis in the dura, I developed methods to culture and grow human dural fibroblasts from dural explants. Changes in T cell populations, including Th1, Th2, Th17 and Tregs, are observed in the aged dura, prompting investigation into the contribution of T cell-derived cytokines to dural fibrosis. Notably, TGFβ, predominantly secreted by Tregs, induced fibrosis in vitro, mirroring observations in aged meninges. Further, AAV-mediated overexpression of a constitutively active TGFβ receptor 1 in mouse dural fibroblasts induced fibrosis around critical CSF access points, potentially leading to impaired CSF drainage and glymphatic function, mimicking aging-related pathology. Investigating potential anti-fibrotic agents, nintedanib and pirfenidone, revealed nintedanib's potential to mitigate fibrosis but raised concerns regarding its impact on lymphatic function. Pirfenidone, with multifaceted anti-fibrotic mechanisms, demonstrated promise in attenuating fibrosis in vitro. However, the complexities of drug effects on lymphatic function warrant further investigation. This study underscores the significance of tissue-specific responses and highlights potential therapeutic avenues for age-related meningeal fibrosis, providing insights into CNS clearance mechanisms in aging and neurodegenerative diseases.
Author: Hitpass Romero, Kate
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7052339670