The Role of Glymphatic Clearance and its Pharmacological Modulation in a Rodent Model of Parkinson’s Disease

• Applicant: Dr. Dennis-Dominik Rosmus
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 582799487

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized not only by motor impairment but also by early non-motor symptoms, including sleep disturbances. Growing evidence suggests that these early alterations may be closely linked to the dysfunction of the glymphatic-lymphatic system - a brain-wide waste clearance pathway that is strongly regulated by sleep and by noradrenergic tone originating from the locus coeruleus (LC). Because LC neurons are among the earliest affected in PD, impaired LC signaling might critically disrupt glymphatic flow long before overt neurodegeneration becomes detectable. This project aims to investigate how sleep abnormalities, LC dysfunction, and glymphatic impairment interact during early α-synucleinopathy. Using a well-established preformed fibril mouse model that recapitulates prodromal PD features, we will combine in vivo imaging, detailed sleep-state analysis, and pharmacological manipulation of noradrenergic signaling. A particular focus will be placed on comparing glymphatic flow in awake and anesthetized mice, as pharmacological silencing of LC activity by anesthesia will allow us to disentangle LC-dependent and LC-independent contributors to glymphatic dysfunction in early PD. Finally, we will test whether enhancing glymphatic clearance with the α2-adrenergic agonist Dexmedetomidine, a clinically approved sedative that promotes CSF flow by suppressing noradrenergic tone, can alleviate α-synuclein pathology, innate immune activation, and sleep disruption. By clarifying how noradrenergic dysregulation and impaired glymphatic clearance contribute to PD pathogenesis, this project seeks to establish the glymphatic-lymphatic system as a novel therapeutic entry point for disease-modifying interventions in early PD from which patients in a clinical setting might benefit in the future.

• DFG Programme: Fellowship
• International Connection: Denmark
• Host: Dr. Maiken Nedergaard