Chen Y, Zhou Y, Bai Y, Jia K, Zhang H, Chen Q, Song M, Dai Y, Shi J, Chen Z, Yan X, Shen Y. Macrophage-derived CTSS drives the age-dependent disruption of the blood-CSF barrier. Neuron. 2025 Apr 2;113(7):1082-1097.e8. Epub 2025 Feb 26 PubMed.
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Weizmann Institute of Science
This paper by Chen and colleagues provides new insight into the delicate balance between immune cells and the brain, particularly at the barriers that serve as physiological interfaces between these two systems. Specifically, the authors focus on how the integrity of the choroid plexus is influenced by macrophages during the aging process.
Over the past decade, it has become increasingly clear that the choroid plexus plays a vital role beyond production of cerebrospinal fluid (CSF); it is necessary for immune surveillance and repair. The authors’ data highlight the communication within this brain-immune interface. This communication is critically regulated by the local environment, as well as by signaling from both the periphery and the brain.
Though monocyte-derived macrophages are needed to support the diseased brain, macrophages residing within the barrier itself are shown here to have a negative impact on the integrity of this barrier in aging. Coupled with existing evidence that aging of the choroid plexus is associated with local brain inflammation affecting microglial fate, this study provides a new perspective on the complexity of these interactions. Further studies are required to explore the characteristics of the macrophages that compromise the integrity of the aged choroid plexus, including their origins and the mechanisms governing their behavior.
View all comments by Michal SchwartzThird Rock Ventures
This paper focuses useful attention on the choroid plexus as a potential contributor to brain aging. The approach taken was to evaluate tight junctions of the CP epithelium, identifying claudin-1 (product of the CLDN1 gene) as declining in abundance with age. Further study showed that CLDN1 transcription was unaffected and that macrophage-derived cathepsin S (CTSS) was increased. The latter accounted for the lowering of CLDN1 and subsequent tight junction barrier dysfunction, which was documented by showing abnormal albumin staining deep into the ependyma, along with increased immune cells in brain parenchyma, fewer Ki67+ cells in the neurogenic subependymal zone (SEZ), and alterations in Barnes maze and tail suspension test. Subsequent experiments involved interventions, such as overexpressing CTSS in young mice or knocking it down in older mice, to perturb CLDN1 levels, leading to predicted outcomes. The authors hypothesize that senescent cell products (SASP) drive macrophage expression of CTSS, so administered senolytics to suppress this signaling, and showed anticipated downstream effects. Oncogene-induced senescence was induced with AAV-HRAS(G12V) to drive the process, again with predicted outcomes. The dataset is formidably extensive and consistent with the hypothesis.
Questions are, however, raised by the experimental approach. The attribution of brain aging readouts to CP barrier dysfunction is based on correlations between CLDN1 or CTSS and parameters of brain aging. Delivery of reagents to perturb CLDN1, CTSS, senescence, or SASP was either oral/systemic or ICV, all of which will affect the ependyma and adjacent parenchyma. As the direct readouts for barrier dysfunction examined the ependyma and subependymal parenchyma, and may affect the downstream phenomena under study, i.e., SEZ cell proliferation, presumably of neuroblasts, Barnes maze, and tail-suspension performance, these features of the dataset leave the role of CP barrier dysfunction in brain aging uncertain.
View all comments by Richard RansohoffMaastricht University
The mechanisms underlying the disruption of the choroid plexus in aging and age-related neurodegenerative diseases remain relatively underexplored. In this insightful study, Chen et al. provide compelling evidence that macrophage activity plays a crucial role in blood-CSF barrier dysfunction during aging.
The choroid plexus is essential for CSF production and plays a key role in maintaining brain homeostasis, primarily through the blood-CSF barrier. Studies have also increasingly highlighted its involvement in immune surveillance and repair. These functions are, among others, supported by resident choroid plexus macrophages.
The choroid plexus undergoes significant structural and functional alterations with aging, including elevated blood-CSF barrier permeability and reduced CSF secretion. Aging also induces a shift toward a pro-inflammatory environment, which impairs immune surveillance and repair and compromises the integrity of the blood-CSF barrier by increasing permeability, decreasing CSF turnover, and promoting the infiltration of peripheral immune cells. The current study builds on this knowledge by revealing that the accumulation of senescent cells in the aging choroid plexus triggers the secretion of cathepsin S by resident choroid plexus macrophages, thereby disrupting the blood-CSF barrier through the degradation of claudin-1, a key component of the epithelial tight junctions of the choroid plexus.
Previous studies have shown that similar structural and functional alterations of the choroid plexus occur during aging and in age-dependent neurodegenerative diseases, such as Alzheimer's disease. However, these changes are often exacerbated in neurodegenerative diseases due to specific brain pathologies. The current study identified increased secretion of cathepsin S with aging. In contrast, our previous proteomics study on APPNL-G-F mice, a knock-in model of Alzheimer’s disease, revealed elevated levels of cathepsin S in the CSF, but not in the choroid plexus (Delvenne et al., 2024).
Therefore, further research is necessary to investigate whether this identified molecular pathway is also present in age-related neurodegenerative diseases. Understanding how disease-specific factors influence macrophage activation and blood-CSF barrier integrity, as well as the underlying mechanisms, will be crucial for identifying therapeutic targets aimed at restoring choroid plexus function and reducing neuroinflammation across age-dependent neurodegenerative diseases.
References:
Delvenne A, Vandendriessche C, Gobom J, Burgelman M, Dujardin P, De Nolf C, Tijms BM, Teunissen CE, Schindler SE, Verhey F, Ramakers I, Martinez-Lage P, Tainta M, Vandenberghe R, Schaeverbeke J, Engelborghs S, De Roeck E, Popp J, Peyratout G, Tsolaki M, Freund-Levi Y, Lovestone S, Streffer J, Bertram L, Blennow K, Zetterberg H, Visser PJ, Vandenbroucke RE, Vos SJ. Involvement of the choroid plexus in Alzheimer's disease pathophysiology: findings from mouse and human proteomic studies. Fluids Barriers CNS. 2024 Jul 18;21(1):58. PubMed.
View all comments by Aurore DelvenneMake a Comment
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