Abstract The choroid plexus (ChP) plays a crucial function in neuroinflammation of the central nervous system and in the immune response of the brain during neurodegeneration. Recent studies described a massive ChP enlargement in patients with multiple sclerosis (MS) and active disease courses, but also in several other neuroinflammatory and neurodegenerative conditions. Nevertheless, the exact basis and pathophysiology behind ChP hypertrophy remains unclear. This study was designed to evaluate the association of cerebrospinal fluid (CSF) proteomic spectra with brain MRI-derived volumetric measures of ChP in two independent cohorts of MS patients, and to translationally validate the related molecular mechanisms in the transcriptomic analysis of the ChP properties in a mouse model of experimental autoimmune encephalomyelitis (EAE). Our analysis revealed five enriched proteins (NTRK2, ADAM23, SCARB2, CPM, CNTN5) significantly associated with the ChP volumes in both of the MS cohorts. These proteins relate closely to mechanisms of cellular communication, function (e.g. transmembrane tyrosine receptor signalling (RTK) and vascular endothelial growth) and pathways involved in the regulation of cellular plasticity (e.g. neuron differentiation, axonal remodelling and myelin regulation) as depicted by molecular function analysis and validation of the results in the transcriptome from ChP tissue specific for EAE. This work provides conclusive new evidence for the role of ChP in the context of neuroinflammation and neurodegeneration, demonstrating the intriguing relationships between ChP enlargement, CSF dynamics, and the development of neuroinflammatory and neurodegenerative diseases. Our results are encouraging for the development of new therapeutic avenues (i.e. targeting RTK signalling). One sentence summary Tyrosine receptor signalling is tightly associated with choroid plexus enlargement and is key in CSF dynamics during a neuroinflammatory attack in MS

Choroid plexus enlargement in acute neuroinflammation is tightly interrelated to the tyrosine receptor signalling