Fluids and Barriers of the CNS最新文献

Neurogranin (Ng), a known regulator of neuronal Ca²⁺-calmodulin (CaM) signaling, is linked to Alzheimer's disease. Though well-studied in neurons, Ng is also expressed in brain vasculature, where its function remains unclear. To investigate Ng's role in brain microvascular endothelial cells, we defined its interactome using immunoprecipitation-mass spectrometry (IP-MS) under high- and low-Ca²⁺ conditions. Among 119 Ng-binding proteins, we discovered a novel interaction between Ng and MYH9, a key regulator of cytoskeletal remodeling. Ng-MYH9 binding was prominent in high Ca²⁺ and validated via CaM affinity pulldown and proximity ligation assays. Ng knockdown reduced F-actin levels, while MYH9 knockdown decreased both Ng and F-actin. Loss of Ng-MYH9 also impaired AKT-GSK3β signaling and elevated the endothelial activation marker VCAM1. Ng-null mice exhibited disrupted brain microvascular architecture and reduced MYH9 expression in endothelial cells. These findings reveal a novel Ng pathway promoting MYH9-dependent cytoskeletal remodeling and a potential role in maintaining blood-brain barrier integrity, a previously unrecognized function for Ng in brain health and Alzheimer's disease.

Background: Brain pericytes, the mural cells of cerebral microvessels, were long regarded as controversial, mainly due to their morphological and functional heterogeneity, plasticity, and variable expression of alpha-smooth muscle actin (α-SMA). However, they have recently emerged as a focal point in neuroscience research owing to their critical roles in regulating the blood-brain barrier (BBB), neuroinflammation, cerebral blood flow (CBF), and angiogenesis. In particular, the regulation of CBF and angiogenesis involves highly dynamic processes such as contraction and migration. By converting chemical energy into mechanical work, motor proteins, like myosin-through their interactions with intracellular filaments, primarily actin-play a crucial role in these processes.

Main body: In this review, we describe the contractile elements of pericytes, highlighting the relevance of α-SMA and myosin II isoforms containing the Myh11 and Myh9 heavy chains. In addition, we discuss recent advances in understanding how distinct pericyte subtypes contribute to mechanical force generation during the regulation of vessel diameter, pericyte migration, and the dynamic remodelling of their cellular processes. Furthermore, we highlight how ensheathing pericytes, which envelop the initial branches of the capillary bed and express high levels of α-SMA, initiate robust vasorelaxation during neurovascular coupling. In contrast, α-SMA-low capillary pericytes regulate basal vascular tone but also actively sense and respond to local glucose levels and neuronal activity. While ensheathing pericytes play a central role in sustained vasoconstriction following ischaemia, capillary pericytes are primarily responsible for secondary vasoconstrictive events during stroke.

Conclusions: Taken together, pericytes are dynamic cells capable of exerting diverse forms of mechanical force, playing essential roles in both physiological and pathological conditions. Eppur si muove-and yet it moves.

Biological barriers play a crucial role in maintaining tissue homeostasis across diverse animal taxa, from invertebrates to mammals. In the nervous system, they regulate ion balance, metabolic exchange, and immune protection, ensuring proper neuronal function. In arthropods, the blood-brain barrier (BBB) is primarily formed by the perineurium, consisting of perineurial and subperineurial glial cells that establish septate junctions to restrict diffusion. Cephalopods, such as octopuses and squids, possess two distinct BBBs: one formed by glial cells and another by pericytes, depending on the type of brain blood vessel. Similarly, in vertebrates such as sharks, skate, rays, and sturgeons, the BB is also formed by glial cells. In contrast, the BBBs of most vertebrates rely on endothelial tight junctions, although astrocytes and pericytes contribute significantly to BBB maintenance and function. Importantly, glial barriers also exist in vertebrates, including the blood-nerve barrier (BNB), and the blood-cerebrospinal fluid barrier (BCSFB). Despite structural differences, the molecular mechanisms governing barrier formation, function, and plasticity show remarkable evolutionary conservation between invertebrates and vertebrates. In this review, we examine the diversity of glial barriers, their structural and functional parallels, evolutionary origins, and the key molecular pathways that regulate their development.

Background: The choroid plexus is a highly vascularized structure located in the lateral, third, and fourth ventricles of the brain. Recent studies suggest that volumetric changes in choroid plexus volume are associated with progression in various brain diseases. Segmentation algorithms have significantly improved our ability to study choroid plexus volumetrics in relation to various pathologies. Thus, the specific purpose of this review was to describe to what extent choroid plexus volume estimation provides clinically relevant information in brain diseases.

Methods: An extensive literature search was conducted across Pubmed, Embase and Cochrane databases. A comprehensive, detailed qualitative descriptive analysis, and a thorough risk-of-bias assessment were performed for the included studies.

Results: Forty-eight studies were included in this systematic review in the categories of multiple sclerosis, neurodegenerative diseases, psychiatric disorders, healthy populations and a group categorized as "other" for all other brain diseases that did not fit into the other categories.

Conclusion: For many of the studies included, the patients had a larger choroid plexus volume compared to healthy controls. Evidence is currently insufficient to determine whether CPV enlargement correlates with clinical severity or functional scores. The most common segmentation technique was the automatic segmentation method, followed by manual correction of the segmented choroid plexus. Thus, this review highlights the growing interest choroid plexus volume, its segmentation, and its potential as a biomarker for numerous brain diseases.

Background: Idiopathic normal pressure hydrocephalus (iNPH) predominantly manifests with gait disturbances, yet clinical assessments are vulnerable to confirmation bias, particularly post-shunt surgery. Blinded video evaluations are a method to enhance objectivity in gait assessment, but their reliability has never been systematically investigated. The aim was to evaluate the inter-rater reliability of blinded gait assessments in iNPH patients and to investigate how these assessments correlate with the Hellström iNPH scale and patient-reported health status following shunt surgery.

Methods: Thirty-nine patients (mean age 75.5 years) diagnosed with iNPH between 2019 and 2023 were recorded performing Timed Up and Go (TUG) test before and after shunt surgery. Patients who required a walking aid were excluded. Four specialized raters, blinded to timepoint, evaluated gait pattern and graded improvement. Inter-rater agreement was quantified by Krippendorff's α; Spearman's ρ assessed correlations between graded improvement, Hellström iNPH scale changes, and EuroQol 5-Dimension 5-Level Visual Analogue Scale (EQ-VAS) differences.

Results: Agreement on video graded improvements was strong (α = 0.80, 95% CI: 0.76-0.84), whereas agreement on specific gait patterns was moderate (α = 0.53, 95% CI: 0.43-0.62). Graded improvement scores correlated moderately with changes in the Hellström iNPH scale (ρ = 0.67, p < 0.01) and showed fair correlation with EQ-VAS (ρ = 0.37, p < 0.01).

Conclusions: Blinded video assessments reliably captured postoperative gait improvements in iNPH and showed strong inter-rater agreement. While specific gait pattern ratings were less consistent, combining structured video scoring with clinical scales can improve outcome evaluation. More refined tools are needed to better detect subtle changes in gait and to reflect patient-perceived recovery.

Cerebrovascular disease, which primarily affects the brain's blood vessels, remains a major global cause of death and disability. Among its clinical manifestations, ischaemic stroke is by far the most common. Prolonged oedema due to blood vessel leakage is detrimental to the delicate neuronal environment throughout the ischaemic and reperfusion phase and contributes to the mortality, morbidity, and disabilities associated with this devastating condition. Under physiological conditions, an intact blood-brain barrier (BBB) protects and regulates solute and cell transit in and out of the central nervous system. Indeed, dysfunction of this formidable cerebrovascular regulator has been functionally linked to adverse outcomes in stroke. While our knowledge of the underlying mechanism is incomplete, increasing evidence, particularly from studies using models of rodents exposed to middle cerebral artery occlusion (MCAO), supports a biphasic breakdown of the BBB in ischemic stroke. However, debate persists regarding the precise mechanisms of BBB dysfunction. Understanding this pathobiology is essential for developing targeted interventions to improve clinical outcomes in stroke patients. In this review, we provide a summary of the structure and function of the BBB as well as the cellular and molecular determinants of leakage pathways present in pathological conditions, and evaluate medical strategies aimed at reducing BBB disruption in stroke. We also discuss the potential for selectively targeting specific phases of BBB leakage.

Aging is a major risk factor for both cardiovascular and neurodegenerative diseases. The bidirectional communication between the heart and brain, commonly referred to as heart-brain crosstalk, is increasingly disrupted with age. In this review, we summarize current evidence linking cardiovascular and neurodegenerative disorders, particularly in the context of aging. We also discuss the underlying mechanisms responsible for the heart-brain crosstalk, including blood-brain barrier breakdown, vascular dysfunction, nervous system alterations, inflammation, and endocrine dysregulation, which may explain the frequent co-occurrence of dysfunction in both organs during aging. Understanding these interconnections provides critical insights into the pathophysiology of age-related diseases and highlights potential therapeutic targets to preserve both heart and brain health in the aging population.

The blood-brain barrier (BBB) is a highly selective interface between the peripheral circulation and the central nervous system (CNS), crucial for maintaining brain homeostasis. Disruptions to the BBB, such as increased permeability or structural damage, can lead to neurological damage. Mitochondria, the primary energy producers within endothelial cells, play a key role in the function of the BBB by maintaining its integrity and low permeability. This review first outlines the structural components of the BBB, then examines the role of mitochondria in endothelial cells under physiological conditions. We further focus on alterations in mitochondrial function during pathological states, discussing their impact on BBB stability. Briefly, this review explores the involvement of mitochondria in BBB endothelial cells in both physiological processes and the pathological progression of neurological diseases, while proposing potential therapeutic directions for treating CNS disorders.

Background: Transferrin receptor (TfR)-mediated transcytosis is a well-established method for delivering biologic therapeutics and diagnostics to the brain. Although moderate affinity towards TfR is beneficial for TfR-mediated brain delivery at therapeutic doses, emerging evidence has indicated that high TfR affinity may be more beneficial at tracer doses. With the development of antibody-based PET radioligands for neurodegenerative diseases, such as Alzheimer's disease, understanding the pharmacokinetics of TfR-binders at tracer dose is essential. Thus, this study aimed to evaluate the effect of TfR affinity on brain uptake at a tracer dose in both wild-type (WT) and amyloid-beta (Aβ) pathology presenting mice and to demonstrate the usability of TfR-mediated brain delivery of immunoPET diagnostic radioligands to visualize intrabrain Aβ pathology in vivo.

Methods: Three different affinity variants of anti-mouse TfR-binding antibody 8D3, engineered by alanine point mutations, were selected. Bispecific antibodies were designed with knob-into-hole technology with one arm targeting TfR (8D3) and the other arm targeting human Aβ (bapineuzumab). Antibody affinities were measured in an in vitro cell assay. In vivo pharmacokinetic analyses of radioiodinated bispecific antibodies and bapineuzumab in brain, blood and peripheral organs were performed over 7 days post-injection in WT mice and a model of Aβ pathology (App^NL-G-F). The strongest TfR affinity bispecific antibody was also evaluated as a positron emission tomography (PET) radioligand for detecting Aβ pathology in WT and App^NL-G-F mice.

Results: The three bispecific antibodies bound to TfR with affinities of 10 nM, 20 nM and 240 nM. Independent of genotype, stronger TfR-affinity resulted in higher initial brain uptake. The two higher-affinity bispecific antibodies behaved similarly and differentiated between WT and App^NL-G-F mice earlier than the lowest affinity variant. Finally, the 10 nM bispecific antibody was able to clearly differentiate between WT and App^NL-G-F mice when used as a PET radioligand.

Conclusion: This study supports the hypothesis that stronger TfR affinity enhances brain uptake at a tracer dose. With the more effective detection of Aβ pathology, stronger TfR affinity is a crucial design feature for future bispecific immunoPET radioligands for intrabrain targets via TfR-mediated transcytosis.