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Targeting monocytic Occludin impairs transendothelial migration and HIV neuroinvasion.
Transmigration of circulating monocytes from the bloodstream to tissues represents an early hallmark of inflammation. This process plays a pivotal role during viral neuroinvasion, encephalitis, and HIV-associated neurocognitive disorders. How monocytes locally unzip endothelial tight junction-associated proteins (TJAPs), without perturbing impermeability, to reach the central nervous system remains poorly understood. Here, we show that human circulating monocytes express the TJAP Occludin (OCLN) to promote transmigration through endothelial cells. We found that human monocytic OCLN (hmOCLN) clusters at monocyte-endothelium interface, while modulation of hmOCLN expression significantly impacts monocyte transmigration. Furthermore, we designed OCLN-derived peptides targeting its extracellular loops (EL) and show that transmigration of treated monocytes is inhibited in vitro and in zebrafish embryos, while preserving vascular integrity. Monocyte transmigration toward the brain is an important process for HIV neuroinvasion and we found that the OCLN-derived peptides significantly inhibit HIV dissemination to cerebral organoids. In conclusion, our study identifies an important role for monocytic OCLN during transmigration and provides a proof-of-concept for the development of mitigation strategies to prevent monocyte infiltration and viral neuroinvasion.
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Single-cell mapping of lipid metabolites using an infrared probe in human-derived model systems.
Understanding metabolic heterogeneity is the key to uncovering the underlying mechanisms of metabolic-related diseases. Current metabolic imaging studies suffer from limitations including low resolution and specificity, and the model systems utilized often lack human relevance. Here, we present a single-cell metabolic imaging platform to enable direct imaging of lipid metabolism with high specificity in various human-derived 2D and 3D culture systems. Through the incorporation of an azide-tagged infrared probe, selective detection of newly synthesized lipids in cells and tissue became possible, while simultaneous fluorescence imaging enabled cell-type identification in complex tissues. In proof-of-concept experiments, newly synthesized lipids were directly visualized in human-relevant model systems among different cell types, mutation status, differentiation stages, and over time. We identified upregulated lipid metabolism in progranulin-knockdown human induced pluripotent stem cells and in their differentiated microglia cells. Furthermore, we observed that neurons in brain organoids exhibited a significantly lower lipid metabolism compared to astrocytes.
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Tight junction protein occludin regulates progenitor Self-Renewal and survival in developing cortex.
Occludin (OCLN) mutations cause human microcephaly and cortical malformation. A tight junction component thought absent in neuroepithelium after neural tube closure, OCLN isoform-specific expression extends into corticogenesis. Full-length and truncated isoforms localize to neuroprogenitor centrosomes, but full-length OCLN transiently localizes to plasma membranes while only truncated OCLN continues at centrosomes throughout neurogenesis. Mimicking human mutations, full-length OCLN depletion in mouse and in human CRISPR/Cas9-edited organoids produce early neuronal differentiation, reduced progenitor self-renewal and increased apoptosis. Human neural progenitors were more severely affected, especially outer radial glial cells, which mouse embryonic cortex lacks. Rodent and human mutant progenitors displayed reduced proliferation and prolonged M-phase. OCLN interacted with mitotic spindle regulators, NuMA and RAN, while full-length OCLN loss impaired spindle pole morphology, astral and mitotic microtubule integrity. Thus, early corticogenesis requires full-length OCLN to regulate centrosome organization and dynamics, revealing a novel role for this tight junction protein in early brain development.
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N-myristoyl Transferase Maintains Type II Neuroblasts through Notch Signaling in Drosophila.
The development of a complex nervous system relies on precisely regulated heterogeneity and population stability among multiple types of neural stem cells (NSCs). In Drosophila melanogaster, the larval NSCs consist of type I neuroblasts (I NBs) and type II neuroblasts (II NBs). While the division pattern of II NB lineages is similar to the cortical expansion of primates, the detailed mechanism governing their maintenance is still not completely understood. Here, we demonstrate that the N-myristoyl transferase (NMT) in Drosophila serves as a critical regulator to maintain II NBs identity through N-myristoylation. Mechanistically, NMT myristoylates the proteasome subunit P26s4 that negatively regulates Hairless, an antagonist of Notch, consequently sustaining normal Notch activity. In human brain organoids, the function of NMT is conserved in the maintenance and proliferation of NSCs. Overall, this research not only reveals significant roles of NMT and N-myristoylation in II NB maintenance but also highlights a novel mechanism of how post-translational modification (PTM) regulates the homeostasis among heterogeneous NSCs during neurogenesis.
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Is Gulf War Illness a prolonged early phase tauopathy?
The work of the Gulf War Illness (GWI) Consortium and that of basic and clinical researchers across the USA have resulted in a better understanding in recent years of the pathological basis of GWI, as well as of the mechanisms underlying the disorder. Among the most concerning symptoms suffered by veterans with GWI are cognitive decrements including those related to memory functioning. These decrements are not severe enough to meet dementia criteria, but there is significant concern that the mild cognitive impairment of these veterans will progress to dementia as they become older. Recent studies on GWI using human brain organoids as well as a rat model suggest that one potential cause of the cognitive problems may be elevated levels of tau in the brain, and this is supported by high levels of tau autoantibodies in the blood of veterans with GWI. There is urgency in finding treatments and preventive strategies for these veterans before they progress to dementia, with added value in doing so because their current status may represent an early phase of tauopathy common to many neurodegenerative diseases.
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Blood‒brain barrier permeability assessment: from biomimetic models to multimodal imaging.
The blood‒brain barrier (BBB) is a vital physiological structure that maintains the microenvironmental homeostasis in the central nervous system (CNS). Imbalances in its permeability play a key role in various neurological disorders, including stroke, neurodegenerative diseases, and brain tumors. The development of precise techniques for assessing BBB permeability is therefore paramount for elucidating the mechanisms of neurological diseases, overcoming drug development challenges, and achieving precise diagnosis and treatment of CNS disorders. This review systematically summarizes the latest advances in the assessment of BBB permeability. Regarding in vitro models, platforms have evolved from the traditional transwell system to microfluidic chips incorporating fluid shear forces and subsequently to highly biomimetic brain organoids, with continuous improvements in the ability to simulate the neurovascular unit (NVU) microenvironment. For in vivo assessment, we detail the principles and applications of imaging techniques, including dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), positron emission tomography (PET), near-infrared II (NIR-II) fluorescence imaging (FI), and two-photon microscopy (TPM), highlighting their complementary strengths in macroscopic quantification, molecular targeting, and microscopic dynamic observation. The integration of multi-modal technologies and precise quantitative assessment is a prominent trend. Future investigations will focus on artificial intelligence (AI)-driven personalized permeability assessment, the development of novel intelligent probes, and the dynamic real-time monitoring of the BBB, thereby providing powerful methodological support for neurological disease research.
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High-throughput screening identifies histone deacetylase inhibitors that modulate GTF2I expression in 7q11.23 microduplication autism spectrum disorder patient-derived cortical neurons.
BACKGROUND: Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition affecting almost 1% of children, and represents a major unmet medical need with no effective drug treatment available. Duplication at 7q11.23 (7Dup), encompassing 26-28 genes, is one of the best characterized ASD-causing copy number variations and offers unique translational opportunities, because the hemideletion of the same interval causes Williams-Beuren syndrome (WBS), a condition defined by hypersociability and language strengths, thereby providing a unique reference to validate treatments for the ASD symptoms. In the above-indicated interval at 7q11.23, defined as WBS critical region, several genes, such as GTF2I, BAZ1B, CLIP2 and EIF4H, emerged as critical for their role in the pathogenesis of WBS and 7Dup both from mouse models and human studies. METHODS: We performed a high-throughput screening of 1478 compounds, including central nervous system agents, epigenetic modulators and experimental substances, on patient-derived cortical glutamatergic neurons differentiated from our cohort of induced pluripotent stem cell lines (iPSCs), monitoring the transcriptional modulation of WBS interval genes, with a special focus on GTF2I, in light of its overriding pathogenic role. The hits identified were validated by measuring gene expression by qRT-PCR and the results were confirmed by western blotting. RESULTS: We identified and selected three histone deacetylase inhibitors (HDACi) that decreased the abnormal expression level of GTF2I in 7Dup cortical glutamatergic neurons differentiated from four genetically different iPSC lines. We confirmed this effect also at the protein level. LIMITATIONS: In this study, we did not address the molecular mechanisms whereby HDAC inhibitors act on GTF2I. The lead compounds identified will now need to be advanced to further testing in additional models, including patient-derived brain organoids and mouse models recapitulating the gene imbalances of the 7q11.23 microduplication, in order to validate their efficacy in rescuing phenotypes across multiple functional layers within a translational pipeline towards clinical use. CONCLUSIONS: These results represent a unique opportunity for the development of a specific class of compounds for treating 7Dup and other forms of intellectual disability and autism.
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Central integration mechanisms of neurovascular unit dysfunction and novel synergistic therapeutic strategies.
The neurovascular unit (NVU) is a highly integrated multicellular complex composed of neurons, astrocytes, microglia, brain microvascular endothelial cells (BMECs), pericytes, and the extracellular matrix (ECM). It forms the structural and functional basis of the blood-brain barrier (BBB) and is pivotal for maintaining the homeostasis of the brain. Traditional neuroprotective strategies targeting individual cell types have shown limited efficacy in central nervous system (CNS) diseases, mainly due to the neglect of intricate intercellular crosstalk within the NVU. In this review, we first systematically summarize the core mechanisms by which the NVU functional unit causes NVU dysfunction in representative acute CNS injuries (ischemic/hemorrhagic stroke, traumatic brain injury), neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, multiple sclerosis), and systemic diseases (diabetic encephalopathy, depression). Based on this, we innovatively summarize and clarify six major cross-disease pathological mechanisms of NVU dysfunction, including intercellular communication disorders, abnormal epigenetic modifications, microbiome-NVU interaction dysregulation, metabolic reprogramming dysfunction, neuroimmune-vascular coupling imbalance, and mechanical microenvironment imbalance. Additionally, we integrate emerging NVU models (co-culture systems, organoids, microfluidic chips, 3D bioprinting) with multi-omics technologies to establish a cross-scale dynamic research paradigm, and propose multicomponent coordinated regulatory strategies for NVU-targeted therapies. This framework aims to expand the understanding of NVU-centered pathological processes across diverse CNS diseases and provides a novel theoretical basis for precise therapeutic interventions, thereby bridging the gap between basic research and clinical translation.
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Forebrain assembloids support the development of fast-spiking human PVALB+ cortical interneurons and uncover schizophrenia-associated defects.
Disruption of parvalbumin positive (PVALB+) cortical interneurons is implicated in the pathogenesis of schizophrenia. However, how these defects emerge during development remains poorly understood. The protracted, postnatal maturation of PVALB+ cortical interneurons has complicated human pluripotent stem cell (hPSC)-based models for studying their role in neuropsychiatric disease. Here, we present a forebrain assembloid system yielding PVALB+ cortical interneurons that match the molecular identity and distinctive electrophysiology of primary PVALB+ interneurons. We further established a series of isogenic hPSC lines carrying structural variants associated with schizophrenia and identified variant-specific phenotypes affecting cortical interneuron migration, the molecular profile of PVALB+ cortical interneurons, and their ability to regulate cortical network activity, including γ-band oscillations. These findings offer plausible mechanisms for how the disruption of cortical interneuron development may impact schizophrenia risk and provide a human experimental platform to study PVALB+ cortical interneurons in health and disease.
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Analysis of gene co-expression connectivity dynamics implicates aberrant neuron-oligodendroglia interactions in schizophrenia.
Dysconnectivity in schizophrenia is a pervasive concept across various levels of systems biology. To better understand disrupted patterns of molecular connectivity in schizophrenia, we apply innovative approaches to gene co-expression networks starting from multiple regions of postmortem brain (bulk RNA-Seq from dorso-lateral prefrontal cortex- (DLPFC) (Ndonors=297; sex: M/F = 212/85), hippocampus (Ndonors=250; sex: M/F = 181/69) and caudate (Ndonors=349; sex: M/F = 242/107). Here we identify differentially connected genes (DCG) in schizophrenia networks that deviate from architectural relationships characteristic of neurotypical gene networks based on three network metrics- total connectivity (kTot), clustering coefficient (C), and intra-module degree (kIn). We find multiple DCG consistent across all brain regions, most of which we then independently confirm in brain single nuclei (snRNAseq) data and in four independent human iPSC-derived brain organoids. DCG specific for each network parameter shows enrichment in schizophrenia genetic signal, in pathways prominently related to neurons and oligodendroglia functionality, and in cell-type specific co-expression patterns that differ between neurotypical and schizophrenia, implicating neuronal-oligodendroglia incoordination.