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.