Investigating the Age-Related Decline of Choroid Plexus Function
The choroid plexus is a structure responsible for producing and filtering cerebrospinal fluid, but likely has other important roles as well. The production of cerebrospinal fluid declines with age for reasons that are not all that well explored. A reduced flow of cerebrospinal fluid through the brain likely contributes to brain aging via an increased presence of the metabolic waste that is normally drained from the brain via cerebrospinal fluid flow. Hence the occasional paper such as this one, in which researchers attempt to make some inroads into mapping the age-related biochemical changes that take place in cells of the choroid plexus, one small step along the way to the construction of a bigger picture view of how aging affects the choroid plexus.
The choroid plexus (CP) is an understudied tissue in the central nervous system and is primarily implicated in cerebrospinal fluid (CSF) production. CP also produces numerous neurotrophic factors (NTF) which circulate to different brain regions. Regulation of NTFs in the CP during natural aging is largely unknown. Here, we investigated the age and gender-specific transcription of NTFs along with the changes in the tight junctional proteins (TJPs) and the water channel protein Aquaporin (AQP1).
CSF is composed of 99% water, and the remaining 1% is accounted for by proteins, ions, neurotransmitters, and glucose. A high water permeability of the blood-cerebrospinal fluid barrier (BCSFB), a physicochemical barrier established by choroid plexus (CP) epithelial cells, is essential for the optimal production of the CSF, and this is met by the abundant expression of water channels AQP4 and AQP1. CSF enters from the perivascular spaces surrounding arteries into the brain parenchyma through the AQP4 water channels in the astrocytic end-feet. AQP1 is a cGMP-gated cation channel that serves as a water channel and a gated ion channel in the choroid plexus, contributing to the regulation of CSF production.
Aging significantly altered NTF gene expression in the CP. Brain-derived neurotrophic factor (BDNF), Midkine (MDK), VGF, Insulin-like growth factor (IGF1), IGF2, Klotho (KL), Erythropoietin (EPO), and its receptor (EPOR) were reduced in the aged CP of males and females. Vascular endothelial growth factor (VEGF) transcription was gender-specific; in males, gene expression was unchanged in the aged CP, while females showed an age-dependent reduction. Age-dependent changes in VEGF localization were evident, from vasculature to epithelial cells. IGF2 and klotho localized in the basolateral membrane of the CP and showed an age-dependent reduction in epithelial cells. Water channel protein AQP1 localized in the tip of epithelial cells and showed an age-related reduction in mRNA and protein levels. TJPs were also reduced in aged mice.
Our study highlights transcriptional level changes in the CP during aging. Altered transcription of the water channel protein AQP1 and TJPs could be involved in reduced CSF production during aging. Importantly, reduction in the neurotrophic factors and longevity factor Klotho can play a role in regulating brain aging.