Department of Biomedicine, University Hospital Basel, University of Basel, Hebelstrasse 20, 4031, Basel, Switzerland.
Department of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland.
Fluids Barriers CNS. 2023 Feb 6;20(1):12. doi: 10.1186/s12987-023-00412-9.
The three-layered meninges cover and protect the central nervous system and form the interface between cerebrospinal fluid and the brain. They are host to a lymphatic system essential for maintaining fluid dynamics inside the cerebrospinal fluid-filled subarachnoid space and across the brain parenchyma via their connection to glymphatic structures. Meningeal fibroblasts lining and traversing the subarachnoid space have direct impact on the composition of the cerebrospinal fluid through endocytotic uptake as well as extensive protein secretion. In addition, the meninges are an active site for immunological processes and act as gatekeeper for immune cells entering the brain. During aging in mice, lymphatic drainage from the brain is less efficient contributing to neurodegenerative processes. Aging also affects the immunological status of the meninges, with increasing numbers of T cells, changing B cell make-up, and altered macrophage complement.
We employed RNASeq to measure gene expression and to identify differentially expressed genes in meninges isolated from young and aged mice. Using Ingenuity pathway, GO term, and MeSH analyses, we identified regulatory pathways and cellular functions in meninges affected by aging.
Aging had profound impact on meningeal gene expression. Pathways related to innate as well as adaptive immunity were affected. We found evidence for increasing numbers of T and B lymphocytes and altered activity profiles for macrophages and other myeloid cells. Furthermore, expression of pro-inflammatory cytokine and chemokine genes increased with aging. Similarly, the complement system seemed to be more active in meninges of aged mice. Altered expression of solute carrier genes pointed to age-dependent changes in cerebrospinal fluid composition. In addition, gene expression for secreted proteins showed age-dependent changes, in particular, genes related to extracellular matrix composition and organization were affected.
Aging has profound effects on meningeal gene expression; thereby affecting the multifaceted functions meninges perform to maintain the homeostasis of the central nervous system. Thus, age-dependent neurodegenerative processes and cognitive decline are potentially in part driven by altered meningeal function.
三层脑膜覆盖并保护中枢神经系统，形成脑脊液与大脑之间的界面。它们是淋巴系统的宿主，该系统对于维持充满脑脊液的蛛网膜下腔内部和穿过脑实质的液体动力学至关重要，通过与神经胶淋巴结构的连接来实现。衬里和穿过蛛网膜下腔的脑膜纤维母细胞通过内吞作用以及广泛的蛋白质分泌，直接影响脑脊液的组成。此外，脑膜是免疫过程的活跃部位，并作为免疫细胞进入大脑的守门员。在小鼠衰老过程中，大脑的淋巴引流效率降低，导致神经退行性过程。衰老还会影响脑膜的免疫状态，增加 T 细胞数量，改变 B 细胞组成，并改变巨噬细胞补体。
我们采用 RNA 测序来测量年轻和年老小鼠脑膜分离物中的基因表达并鉴定差异表达基因。使用 Ingenuity 通路、GO 术语和 MeSH 分析，我们确定了受衰老影响的脑膜中的调节通路和细胞功能。
衰老对脑膜基因表达有深远影响。涉及固有和适应性免疫的途径受到影响。我们发现 T 和 B 淋巴细胞数量增加的证据，以及巨噬细胞和其他髓样细胞活性谱的改变。此外，随着衰老，促炎细胞因子和趋化因子基因的表达增加。同样，补体系统在老年小鼠的脑膜中似乎更活跃。溶质载体基因的表达改变表明脑脊液成分随年龄变化。此外，分泌蛋白的基因表达显示出年龄依赖性变化，特别是与细胞外基质组成和组织相关的基因受到影响。
衰老对脑膜基因表达有深远影响；从而影响脑膜执行多种功能以维持中枢神经系统内环境稳定。因此，年龄依赖性神经退行性过程和认知能力下降可能部分是由脑膜功能改变引起的。
