Choroid plexus (ChP), the brain structure primarily responsible for cerebrospinal fluid production, contains a robust circadian clock, whose role remains to be elucidated. The aim of our study was to [1] identify rhythmically controlled cellular processes in the mouse ChP and [2] assess the role and nature of signals derived from the master clock in the suprachiasmatic nuclei (SCN) that control ChP rhythms. To accomplish this goal, we used various mouse models (WT, mPer2Luc, ChP-specific Bmal1 knockout) and combined multiple experimental approaches, including surgical lesion of the SCN (SCNx), time-resolved transcriptomics, and single cell luminescence microscopy. In ChP of control (Ctrl) mice collected every 4 h over 2 circadian cycles in darkness, we found that the ChP clock regulates many processes, including the cerebrospinal fluid circadian secretome, precisely times endoplasmic reticulum stress response, and controls genes involved in neurodegenerative diseases (Alzheimer's disease, Huntington's disease, and frontotemporal dementia). In ChP of SCNx mice, the rhythmicity detected in vivo and ex vivo was severely dampened to a comparable extent as in mice with ChP-specific Bmal1 knockout, and the dampened cellular rhythms were restored by daily injections of dexamethasone in mice. Our data demonstrate that the ChP clock controls tissue-specific gene expression and is strongly dependent on the presence of a functional connection with the SCN. The results may contribute to the search for a novel link between ChP clock disruption and impaired brain health.

• Klíčová slova
• mPer2 Luc mouse, Choroid plexus, Circadian clock, Circadian transcriptome, Glucocorticoid, Mouse, Suprachiasmatic nuclei,
• MeSH
• cirkadiánní hodiny * fyziologie   MeSH
• cirkadiánní rytmus fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• nucleus suprachiasmaticus * metabolismus   fyziologie   MeSH
• plexus chorioideus * metabolismus   fyziologie   MeSH
• transkripční faktory ARNTL metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Bmal1 protein, mouse MeSH Prohlížeč
• transkripční faktory ARNTL MeSH

The choroid plexus (ChP) produces and is bathed in the cerebrospinal fluid (CSF), which in aging and Alzheimer's disease (AD) shows extensive proteomic alterations including evidence of inflammation. Considering inflammation hampers functions of the involved tissues, the CSF abnormalities reported in these conditions are suggestive of ChP injury. Indeed, several studies document ChP damage in aging and AD, which nevertheless remains to be systematically characterized. We here report that the changes elicited in the CSF by AD are consistent with a perturbed aging process and accompanied by aberrant accumulation of inflammatory signals and metabolically active proteins in the ChP. Magnetic resonance imaging (MRI) imaging shows that these molecular aberrancies correspond to significant remodeling of ChP in AD, which correlates with aging and cognitive decline. Collectively, our preliminary post-mortem and in vivo findings reveal a repertoire of ChP pathologies indicative of its dysfunction and involvement in the pathogenesis of AD. HIGHLIGHTS: Cerebrospinal fluid changes associated with aging are perturbed in Alzheimer's disease Paradoxically, in Alzheimer's disease, the choroid plexus exhibits increased cytokine levels without evidence of inflammatory activation or infiltrates In Alzheimer's disease, increased choroid plexus volumes correlate with age and cognitive performance.

• Klíčová slova
• Alzheimer's disease, aging, cerebrospinal fluid, choroid plexus, pathology,
• MeSH
• Alzheimerova nemoc * patologie   MeSH
• lidé MeSH
• plexus chorioideus metabolismus   patologie   MeSH
• proteomika MeSH
• stárnutí MeSH
• zánět MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

INTRODUCTION: Choroid plexus (CP)-related mechanisms have been implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease. In this pilot study, we aimed to elucidate the association between longitudinal changes in CP volume, sex and cognitive impairment. METHODS: We assessed longitudinal changes in CP volume in a cohort of n = 613 subjects across n = 2,334 datapoints from ADNI 2 and ADNI-GO, belonging to cognitively unimpaired (CN), stable mild cognitive impairment (MCI), clinically diagnosed Alzheimer's disease dementia (AD) or convertor (to either AD or MCI) subgroups. CP volume was automatically segmented and used as a response variable in linear mixed effect models with random intercept clustered by patient identity. Temporal effects of select variables were assessed by interactions and subgroup analyses. RESULTS: We found an overall significant increase of CP volume in time (14.92 mm3 per year, 95% confidence interval, CI (11.05, 18.77), p < 0.001). Sex-disaggregated results showed an annual rate of increase 9.48 mm3 in males [95% CI (4.08, 14.87), p < 0.001], and 20.43 mm3 in females [95% CI (14.91, 25.93), p < 0.001], indicating more than double the rate of increase in females, which appeared independent of other temporal variables. The only diagnostic group with a significant CP increase as compared to CN was the convertors group, with an increase of 24.88 mm3/year [95% CI (14, 35.82), p < 0.001]. ApoE exhibited a significant temporal effect, with the E4 homozygote group's CP increasing at more than triple the rate of non-carrier or heterozygote groups [40.72, 95% CI (25.97, 55.46), p < 0.001 vs. 12.52, 95% CI (8.02, 17.02), p < 0.001 for ApoE E4 homozygotes and E4 non-carriers, respectively], and may have modified the diagnostic group relationship. CONCLUSION: Our results contribute to potential mechanisms for sex differences in cognitive impairment with a novel finding of twice the annual choroid plexus enlargement in females and provide putative support for CP-related mechanisms of cognitive deterioration and its relationship to ApoE E4.

• Klíčová slova
• Alzheimer’s disease, choroid plexus, cognitive impairment, longitudinal analysis, sex differences,
• Publikační typ
• časopisecké články MeSH

Adult neurogenesis is the life-long process of neural stem cell proliferation, differentiation into neurons, migration, and incorporation into the existing neuronal circuits. After decades of research, it is now widely accepted that mammals and birds retain the capacity to regenerate neurons even after their subadult ontogeny. Cerebrospinal fluid participates in the regulation of the neurogenic niches of the vertebrate brain through signaling pathways not fully elucidated. Proteomic studies of cerebrospinal fluid have the potential to allow the in-depth characterization of its molecular composition. Comparative studies help to delineate those pathways that are universally critical for the regulation of neurogenesis in adulthood. In this review, we performed literature-based data mining in studies using liquid chromatography-tandem mass spectroscopy that analyzed cerebrospinal fluid samples from healthy adult humans (Homo sapiens); mice (Mus musculus); sheep (Ovis aries); chickens (Gallus gallus); and two parrot species, the budgerigar (Melopsittacus undulatus) and cockatiel (Nymphicus hollandicus). We identified up to 911 proteins represented in cerebrospinal fluid, involved in various pathways regulating adult neurogenesis. However, only 196 proteins were common across humans, mice, and birds. Pathway components involved in nervous system development, cell migration, and axonal guidance were commonly evident in all species investigated so far. Extensive bioinformatic analysis revealed that the universally over-represented pathways involved L1 cell adhesion molecule protein interactions, cell-adhesion molecules, signals regulating extracellular matrix remodeling, regulation of insulin growth factor signaling, axonal guidance, programmed cell death, immune signaling, and post-translational modifications. Most of the reported proteins are part of extracellular vesicles enriched in cerebrospinal fluid. However, the information presently available is still highly fragmentary, and far more questions persist than are answered. Technological advances will allow cerebrospinal fluid comparative proteomic research to delve into the fundamental processes of adult neurogenesis and eventually translate this research into any regenerative interventions.

• Klíčová slova
• adult neurogenesis, birds, cerebrospinal fluid, chicken, comparative proteomics, human, mammals, mass spectrometry, parrots,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

The choroid plexus (ChP) in each brain ventricle produces cerebrospinal fluid (CSF) and forms the blood-CSF barrier. Here, we construct a single-cell and spatial atlas of each ChP in the developing, adult, and aged mouse brain. We delineate diverse cell types, subtypes, cell states, and expression programs in epithelial and mesenchymal cells across ages and ventricles. In the developing ChP, we predict a common progenitor pool for epithelial and neuronal cells, validated by lineage tracing. Epithelial and fibroblast cells show regionalized expression by ventricle, starting at embryonic stages and persisting with age, with a dramatic transcriptional shift with maturation, and a smaller shift in each aged cell type. With aging, epithelial cells upregulate host-defense programs, and resident macrophages upregulate interleukin-1β (IL-1β) signaling genes. Our atlas reveals cellular diversity, architecture and signaling across ventricles during development, maturation, and aging of the ChP-brain barrier.

• Klíčová slova
• aging, brain barrier, cerebrospinal fluid, choroid plexus, development, single-cell RNA sequencing, single-nucleus RNA sequencing,
• MeSH
• analýza jednotlivých buněk MeSH
• buněčná diferenciace genetika   MeSH
• buněčný rodokmen genetika   MeSH
• epitelové buňky metabolismus   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• mozek metabolismus   fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši embryologie   MeSH
• nemoci mozku genetika   patofyziologie   MeSH
• plexus chorioideus embryologie   metabolismus   fyziologie   MeSH
• signální transdukce MeSH
• stárnutí fyziologie   MeSH
• věkové faktory MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši embryologie   MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH

The choroid plexus (ChP) produces cerebrospinal fluid and forms an essential brain barrier. ChP tissues form in each brain ventricle, each one adopting a distinct shape, but remarkably little is known about the mechanisms underlying ChP development. Here, we show that epithelial WNT5A is crucial for determining fourth ventricle (4V) ChP morphogenesis and size in mouse. Systemic Wnt5a knockout, or forced Wnt5a overexpression beginning at embryonic day 10.5, profoundly reduced ChP size and development. However, Wnt5a expression was enriched in Foxj1-positive epithelial cells of 4V ChP plexus, and its conditional deletion in these cells affected the branched, villous morphology of the 4V ChP. We found that WNT5A was enriched in epithelial cells localized to the distal tips of 4V ChP villi, where WNT5A acted locally to activate non-canonical WNT signaling via ROR1 and ROR2 receptors. During 4V ChP development, MEIS1 bound to the proximal Wnt5a promoter, and gain- and loss-of-function approaches demonstrated that MEIS1 regulated Wnt5a expression. Collectively, our findings demonstrate a dual function of WNT5A in ChP development and identify MEIS transcription factors as upstream regulators of Wnt5a in the 4V ChP epithelium.

• Klíčová slova
• Choroid plexus, Epithelium, Meis1, Meis2, Morphogenesis, WNT5a,
• MeSH
• buněčné linie MeSH
• CRISPR-Cas systémy genetika   MeSH
• čtvrtá mozková komora embryologie   MeSH
• epitel metabolismus   MeSH
• epitelové buňky metabolismus   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• mozek embryologie   MeSH
• myši knockoutované MeSH
• myši MeSH
• plexus chorioideus embryologie   MeSH
• promotorové oblasti (genetika) genetika   MeSH
• protein Wnt 5a genetika   metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• sirotčí receptory podobné receptoru tyrosinkinasy metabolismus   MeSH
• transkripční faktor Meis1 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• Meis1 protein, mouse MeSH Prohlížeč
• protein Wnt 5a MeSH
• Ror1 protein, mouse MeSH Prohlížeč
• Ror2 protein, mouse MeSH Prohlížeč
• sirotčí receptory podobné receptoru tyrosinkinasy MeSH
• transkripční faktor Meis1 MeSH
• Wnt5a protein, mouse MeSH Prohlížeč

Cerebrospinal fluid (CSF) is the liquid that fills the brain ventricles. CSF represents not only a mechanical brain protection but also a rich source of signalling factors modulating diverse processes during brain development and adulthood. The choroid plexus (CP) is a major source of CSF and as such it has recently emerged as an important mediator of extracellular signalling within the brain. Growing interest in the CP revealed its capacity to release a broad variety of bioactive molecules that, via CSF, regulate processes across the whole central nervous system (CNS). Moreover, CP has been also recognized as a sensor, responding to altered composition of CSF associated with changes in the patterns of CNS activity. In this review, we summarize the recent advances in our understanding of the CP as a signalling centre that mediates long-range communication in the CNS. By providing a detailed account of the CP secretory repertoire, we describe how the CP contributes to the regulation of the extracellular environment-in the context of both the embryonal as well as the adult CNS. We highlight the role of the CP as an important regulator of CNS function that acts via CSF-mediated signalling. Further studies of CP-CSF signalling hold the potential to provide key insights into the biology of the CNS, with implications for better understanding and treatment of neuropathological conditions.

• Klíčová slova
• cerebrospinal fluid, choroid plexus, secretion,
• MeSH
• biologický transport fyziologie   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• lidé MeSH
• plexus chorioideus metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH