Annals of the American Thoracic Society

Despite increasing interest the last years, the choroid plexus still is a relatively understudied tissue in neuroscience. The choroid plexus contains fenestrated capillaries surrounded by tightly connected choroid plexus epithelial cells that form the blood–cerebrospinal fluid barrier. The choroid plexus is the main source of cerebrospinal fluid production, assures removal of toxic waste products, and acts as gatekeeper of the brain by the presence of resident inflammatory cells. Increasing evidence shows that choroid plexus’ dysfunction, via altered secretory, transport, immune, and barrier function, plays a central role in a very diverse set of clinical conditions such as aging and the age-associated Alzheimer’s disease. Indeed, age-related changes may weaken the barrier formed by the choroid plexus epithelial cells and/or impair the choroid plexus’ ability to generate cerebrospinal fluid and to produce beneficial factors. Consequently, advanced knowledge of the choroid plexus–cerebrospinal fluid system in aging is essential to better understand age-associated neurological diseases and might open up new therapeutic strategies.

The choroid plexus is a highly vascularized structure that protrudes in the lateral, third, and fourth ventricles of the brain and plays a central role in both health and disease (113). The choroid plexus (Figure 1) consists of a single layer of cuboidal choroid plexus epithelial cells surrounding fenestrated capillaries and loose connective tissue, together with resident macrophages and dendritic cells in the stromal matrix (14). In addition, epiplexus (or Kolmer) cells are highly polymorphic cells that lie on the ventricular surface of the choroid epithelium and have macrophage-like functions. The choroid plexus epithelial cells are polarized due to the presence of tight junctions and contain microvilli at their apical side and a basolateral labyrinth at their basal side (14). These brush border microvilli, along with the basolateral labyrinth, greatly increase the amount of surface area shared by the choroid plexus with both the periphery and the brain (14). This ensures that the choroid plexus is perfectly positioned for its main function, namely the production of cerebrospinal fluid (CSF). This CSF production is the result of the concerted action of a variety of integral membrane proteins that mediate the transepithelial movement of solutes and water across the epithelium (15). In addition, the transport of organic solutes and nutrients, together with the release of proteins and hormones, determines the final CSF composition. Finally, the choroid plexus epithelial cells are able to produce and release extracellular vesicles into the CSF (16), and we recently showed that this extracellular vesicle release is altered in response to inflammation (17). Extracellular vesicles, including exosomes, are nano-sized, membrane-surrounded structures released by cells that are part of the normal cell-to-cell communication by transporting a broad spectrum of bioactive molecules (including proteins and nucleic acids) over long and short distances. Choroid plexus–derived exosomes were shown to play a role in the transfer of folate to the brain through receptor-mediated endocytosis followed by transcytosis (16). In addition, choroid plexus–derived extracellular vesicles also carry several proteins (e.g., TTR) and miRNAs (e.g., miR-155) produced by the choroid plexus cells (17). The CSF is formed at a rate of approximately 0.4 ml/min/g tissue and is replaced three to four times per day, making the choroid plexus epithelial cells among the most efficient tissues in terms of secretory rate (15). Importantly, the choroid plexus also acts as a filtration system and removes toxic molecules, such as metabolic waste, foreign substances (antigens), and excess neurotransmitters, from the CSF, thereby ensuring the maintenance of the delicate environment of the brain.

Aging is a complex, multifactorial process characterized by progressive loss of physiologic integrity and leading to decreased function and increased vulnerability to death (18). One important aspect associated with aging is the presences of chronic, low-grade inflammation, a phenomenon called “inflammaging” (19); this has also been described in the central nervous system (CNS) (20). A fair amount of research has shown that aging severely affects the choroid plexus’ functions, and that this dysfunction is a contributing factor in age-related diseases such as Alzheimer’s (reviewed in References 1 and 4). Reported age-associated changes at the choroid plexus include, but are not limited to, changes in choroid plexus epithelium morphology (4), reduced CSF production and turnover (21), changes in choroid plexus’ secretome (22), loss of barrier integrity (23), increased type I interferon (IFN) signaling (24), and a shift to helper Th2-related response (25).

Several morphologic alterations have been described, including cellular atrophy, irregular nuclei, microvilli shortening, choroidal calcification, thickening of the basement membrane, the presence of collagen deposits in the stroma between epithelial and endothelial cells, and the presence of lipofuscin deposits, lipid droplets, and cytoplasmic protein inclusions called Biondi ring tangles in the epithelial cells (4). The age-associated reduction in contact area between blood–choroid plexus epithelium and choroid plexus epithelium–CSF due to the morphologic alterations, together with the reported changes in molecules involved in CSF production (26), negatively influence CSF production. Indeed, an age-related reduction in CSF production was observed in aging sheep, rodents, and humans (27, 28). Numerous proteins are involved in choroidal CSF production, and a reduction in expression of carbonic anhydrase II, aquaporin 1, and choroidal Na+-K+ ATPase—three choroidal proteins involved in CSF secretion—was found in aged rats (26).

Changes in CSF composition will affect the brain. Interestingly, adult neural stem cells in the ventricular–subventricular zone make contact with the CSF. Not much is known about how molecules secreted by the adult choroid plexus, the major site of CSF synthesis, contribute as modulators of subventricular zone adult neurogenesis (reviewed in Reference 29). Recently, this was explored by the group of Fiona Doetsch in light of age-associated changes in the choroid plexus (22). Their work revealed that the lateral ventricle choroid plexus directly affects neural stem cell behavior by the secretion of factors that promote colony formation and proliferation of quiescent and activated ventricular–subventricular zone stem cells and transit-amplifying cells. Intriguingly, the aged lateral ventricle choroid plexus’ secretome induced a shift in progenitor status, loss of cycling adult neural stem cells, and the appearance of senescence. Transcriptome analysis of the aged lateral ventricle choroid plexus and analysis of its secretome revealed several proteins (e.g., BMP5 and IGF1) that might play a role in the age-associated changes on the adult neural stem cells. Together, their data highlight the key role of the choroid plexus in global brain physiology, and raise the question whether rejuvenating the choroid plexus might be a plausible strategy to restore brain function upon aging. However, more research is needed to identify strategies to reverse the age-associated secretome changes. In addition, our recent findings that inflammation induces changes in choroid plexus–mediated extracellular vesicle production (17), and the observation of increased Il1b gene expression (a typical cytokine associated with inflammation) in the aged choroid plexus (22), raises the question of whether extracellular vesicles play a role in the age-dependent effects of the choroid plexus secretome.

The study of Silva-Vargas and colleagues showed that the age-associated changes were due to choroid plexus’ secretome alterations and not to factors present in blood, which also can affect subventricular zone proliferation (22). As an example, in vivo, bloodborne substances might invade into the CSF if the barrier integrity of the blood–CSF barrier is compromised by aging, thereby affecting brain homeostasis. Our group and others reported on increased blood–CSF barrier permeability in response to inflammatory triggers such as lipopolysaccharide (6, 11) and β-amyloid oligomers (5). Also aging, due to the presence of inflammaging (19), might be associated with loss of barrier function. In agreement with this, a study in sheep revealed increased passive blood–CSF permeability for small and medium-sized molecules upon aging (23).

CSF turnover, calculated by dividing the CSF production rate by the total CSF volume, substantially decreases with age (21, 30), which may have consequences for clearance of many toxic peptides, proteins, and other metabolites. Of note, not only changes in CSF production rate, but also the CSF flow, might be essential in how the (aging) choroid plexus affects brain homeostasis. CSF directional flow through the ventricles is driven by a continuous CSF secretion into the ventricles combined with orchestrated beating of cilia present on the ependymal cells lining the ventricles. This beating creates a network of fluid flows that allows for precise transport within the ventricle, which may control substance distribution in the ventricle (31). Interestingly, transient local changes in the beating pattern were shown to evoke a major change in ventricular flow (31). However, it remains to be determined whether changes in cilia beating pattern occur in aging and whether this, together with the reduced CSF production, affects distribution of locally released compounds throughout the brain.

The group of Michal Schwartz reported that the choroid plexus is indeed essential in brain aging (24). Analysis of both mice and human samples revealed increased type I interferon (IFN) and decreased type II IFN–related gene expression, specifically in the choroid plexus. Interestingly, parabiosis and in vitro experiments suggest that type II IFN–related signals come from the periphery, while factors inducing the type I IFN genes originate in the brain. Strikingly, blockage of IFNAR1 signaling by intracerebroventricular injection was able to improve memory and hippocampal neurogenesis, to diminish astrogliosis and microgliosis, and to increase the antiinflammatory cytokine IL-10. Thus, chronic activation of IFN type I response suppresses IFN type II activity in the aged choroid plexus, which eventually results in increased brain inflammation and cognitive decline. However, further research is needed to determine the therapeutic value of this approach and to identify what induces this specific type I IFN signaling in the choroid plexus.

The vasculature inside the choroid plexus is fenestrated due to the lack of tight junctions. This, together with the high local blood flow rate (∼ 5–10 times greater compared with that of other tissues), allows circulating immune cells to easily transmigrate across the endothelium to enter the stromal matrix (32). Consequently, the choroid plexus is perfectly equipped and located to provide continuous immune surveillance and to regulate immune cell trafficking in response to disease, serving as a gateway for immune cell trafficking into the CSF (3). Under physiological conditions, the choroid plexus is populated with a broad repertoire of CNS-specific CD4+ T cell clones. Analysis of these T cells showed that aging had no effect on the overall specificity of choroid plexus–resident T cells toward CNS antigens. However, Baruch and colleagues did observe a shift toward a dominance of the Th2-related response in the aged choroid plexus, reflected by reduced production of IFN-γ and increased production of IL-4, thereby negatively affecting brain function (25). Importantly, to gain access to the CSF, cells must traverse the cuboidal choroid plexus epithelial cells, which in contrast to the choroid plexus endothelial cells do express tight junctions. As mentioned above, aging is associated with loss of barrier integrity (23), but it remains to be determined whether this is linked to increased immune cell trafficking across the blood–CSF barrier as described for other inflammation-associated diseases (3). However, one should realize that other mechanisms than increased barrier permeability might determine leukocyte migration across the blood–CSF barrier; it has, for example, been shown that elevated cerebral nitric oxide (NO) negatively regulates the choroid plexus gateway activity for immune cell trafficking to the CNS (33).

In conclusion, increasing evidence points to a central role of the choroid plexus in the aging brain due to age-associated alterations in its secretory, transport, immune, and barrier function. Interestingly, choroid plexus transplantation has shown beneficial effects in several neuroinflammatory and neurodegenerative diseases, such as stroke (34), Huntington’s disease (35), and Alzheimer’s disease (36, 37). However, it will be essential to determine how the choroid plexus epithelial cells can be rejuvenated, and whether restoring choroid plexus function is sufficient to completely restore normal brain homeostasis and function.

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Correspondence and requests for reprints should be addressed to Roosmarijn E. Vandenbroucke, Ph.D., VIB–Ghent University, FSVM Building, Technologiepark 927, B-9052 Zwijnaarde (Ghent), Belgium. E-mail:

Author disclosures are available with the text of this article at www.atsjournals.org.

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Annals of the American Thoracic Society
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