Morphological and mitochondrial changes in murine choroid plexus epithelial cells during healthy aging

Abstract

Background Choroid plexuses (ChPs) are intraventricular structures mainly composed by specialized epithelial cells interconnected by tight junctions that establish the blood-cerebrospinal fluid (CSF) barrier. ChPs are essential to produce CSF and transport solutes from and into the brain. Deterioration of ChP function and morphology has been correlated to worsening of neurodegenerative disorders. We here map morpho-functional changes in the ChP epithelial cells during healthy aging, starting from young adult to 2-years old mice. Methods We used a multi-tiered approach, including transmission electron microscopy (TEM), immunohistochemistry, RT-qPCR, Western Blot and 2-photon microscopy (2-PM) at multiple timepoints ranging from young adult to 2-years old mice. Results We identified distinct morpho-functional modifications in epithelial cells of ChP starting from 8 to 12 months of age, which mostly remained stable up to 2 years. These changes include flattening of the epithelium, reduction of microvilli length and an augmentation of interrupted tight junctions. We also found a decrease in mitochondria density together with elongation of mitochondria in older mice. Morphological mitochondrial rearrangements were accompanied by increased superoxide levels, decreased membrane potential and decreased mitochondrial motility in aged mice. Interestingly, most of the age-related changes were not accompanied by modification of protein and/or gene expression levels and aged mitochondria effectively responded to acute pharmacological stressful stimuli. Conclusions Our study suggests a long-term progression of multiple morpho-functional features of the mouse choroid plexus epithelium during adulthood followed by structural remodeling during the aging process. These findings can lead to a better understanding on how functional and morphological rearrangements of ChP are correlated during aging.

Mechanisms of cerebrospinal fluid and brain interstitial fluid production

“…Serot et al ( Serot et al, 2000 ) found the effect of aging on epithelial flattening was exacerbated with Alzheimer’s disease. Scarpetta et al ( Scarpetta et al, 2023a ) have also recently reported reductions in microvilli height and reduced mitochondria density with aging in mice. Many CP ion transporters are energy dependent implying that the lower mitochondrial content may reduce ion transport and, thus, CSF secretion.…”

“…Changes in CSF secretion rate with age are associated with altered CP epithelial structure/function. Thus, the CP epithelium becomes flattened with a thicker basement membrane during aging in human and rodents ( Preston, 2001 ; Scarpetta et al, 2023b ; Serot et al, 2000 ). Serot et al ( Serot et al, 2000 ) found the effect of aging on epithelial flattening was exacerbated with Alzheimer’s disease.…”

Breakthroughs in choroid plexus and CSF biology from the first European Choroid plexus Scientific Forum (ECSF)

“…During development and aging, ChP epithelial cells undergo complex morphological transformations, including the regression of the ciliary axonemes over time, shortening of microvilli and overall cell flattening in mice. Elongation of mitochondria shape was also observed with aging [ 39 ]. Zebrafish ChP cells also undergo complex morphological transformation during development with the acquisition of a multiciliated fate [ 7 , 16 ].…”

Transporters, Ion Channels, and Junctional Proteins in Choroid Plexus Epithelial Cells

“…CPEs of elderly humans are known to exhibit decreases in the total volume, height, and length of apical villi, compared with cells of younger people [9,12]. Scarpetta et al [75] reported age-related changes in murine CPEs, such as flattening of epithelial cells, reduction in microvilli length, an increase in interrupted TJs, and a decrease in mitochondrial density with elongation of mitochondria [75]. These morphological mitochondrial alterations were accompanied by increased superoxide levels and a decreased membrane potential [75].…”

“…Scarpetta et al [75] reported age-related changes in murine CPEs, such as flattening of epithelial cells, reduction in microvilli length, an increase in interrupted TJs, and a decrease in mitochondrial density with elongation of mitochondria [75]. These morphological mitochondrial alterations were accompanied by increased superoxide levels and a decreased membrane potential [75]. Wakamatsu et al [33] reported that immunoreactivities for osteopontin and collagen were present in the densely fibrous or calcified CP stroma of aged human brains.…”