Blocking meningeal lymphatic drainage aggravates Parkinson’s disease-like pathology in mice overexpressing mutated α-synuclein

Abstract

Background Abnormal aggregation of brain α-synuclein is a central step in the pathogenesis of Parkinson’s disease (PD), thus, it is reliable to promote the clearance of α-synuclein to prevent and treat PD. Recent studies have revealed an essential role of glymphatic system and meningeal lymphatic vessels in the clearance of brain macromolecules, however, their pathophysiological aspects remain elusive. Method Meningeal lymphatic drainage of 18-week-old A53T mice was blocked via ligating the deep cervical lymph nodes. Six weeks later, glymphatic functions and PD-like phenotypes were systemically analyzed. Results Glymphatic influx of cerebrospinal fluid tracer was reduced in A53T mice, accompanied with perivascular aggregation of α-synuclein and impaired polarization of aquaporin 4 expression in substantia nigra. Cervical lymphatic ligation aggravated glymphatic dysfunction of A53T mice, causing more severe accumulation of α-synuclein, glial activation, inflammation, dopaminergic neuronal loss and motor deficits. Conclusion The results suggest that brain lymphatic clearance dysfunction may be an aggravating factor in PD pathology. Electronic supplementary material The online version of this article (10.1186/s40035-019-0147-y) contains supplementary material, which is available to authorized users.

The anatomy and metabolome of the lymphatic system in the brain in health and disease

“…Therefore, brain lymphatic vessels play an important role in collecting brain metabolites, draining waste products into nearby lymph nodes and helping the brain maintain homeostasis. Moreover, it has been demonstrated that brain lymphatic clearance dysfunction could participate in the pathogenesis of neurodegenerative diseases . In line with this, we demonstrated that the BLF metabolomes from a PD model group and a control group were indeed different.…”

Subdural haematomas drain into the extracranial lymphatic system through the meningeal lymphatic vessels

“…Previous studies have proven that deep cervical lymph nodes (dCLNs) represent an important site for the drainage of mLVs from intracranial structures to the extracranial lymphatic system [5,23,24]. Different substances, such as macromolecules, fluoresceins and Evans Blue (EB), can be detected in dCLNs when they are drained through mLVs [24,43] . Furthermore, the drainage function of mLVs is significantly decreased after ligating deep cervical lymph vessels (dCLVs) [5,43], suggesting that the presence of the pathway can be indirectly demonstrated by the detection of substances in dCLNs that are injected into the subdural space.…”

Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

“…Importantly, studies using in vivo magnetic resonance imaging (MRI) techniques have also identified the existence of meningeal lymphatic vessels in both humans and nonhuman primates [24,25]. More recent studies have also shown that the meningeal lymphatic system is critical for clearing amyloid beta, extracellular tau, and alpha synuclein from the brain, and that disruption of this drainage system can promote the accumulation of these neurotoxic DAMPs in the brain [21,26,27]. Whether meningeal lymphatic dysfunction plays a role in TBI currently remains poorly understood.…”