Studies on structural and functional changes of mouse choroid plexus in the initiation of neuroinflammation

Abstract

Neuroinflammation has been considered a common denominator and crucial player in neurodegeneration observed in various central nervous system (CNS) disorders. Considering the increasing evidence on the role of choroid plexus (CP) in neuroinflammatory processes through alterations in morphology and functionality of the choroid plexus epithelial (CPE) cells, the main goal of this thesis was to test the contribution of the CP in the initiation of neuroinflammation in two animal models of neuroinflammation-associated diseases: a model of Alzheimer’s disease, induced by intracerebroventricularly (i.c.v.) injected amyloid beta oligomers (AβO) and a lipopolysaccharide (LPS) induced sepsis animal model of systemic inflammation. Main findings from this research conclude that blood cerebrospinal fluid barrier (BCSFB) permeability is increased upon AβO injection, resulting from the loss of typical cuboidal morphology of CPE cells and a decrease in expression of tight junctions components. In the CP, upregulation of gene expression for various cytokines was observed, as well as their increased levels in the cerebrospinal fluid (CSF). Also, increase in gene expression for several matrix metalloproteinases (MMP) in the CP, and in MMP activity in the CSF was noted. After i.c.v. injection of broad spectrum MMP inhibitor with AβO, prevention of AβO-induced BCSFB permeability was found. In accordance with this, increase in BCSFB permeability upon AβO injection was observed in MMP3 deficient mice, but to a lesser extent. Furthermore, an increase in the number of particles in the CSF and an increase in gene expression of extracellular vesicles (EV) markers and miR-155 was found in the CP. A similar pattern of changes in the CP was observed in response to LPS injection compared to AβO injection. The results of this study revealed a significant role for the CP in the initiation of neuroinflammation, through structural and functional changes, in two different models associated with neuroinflammation.