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Splicing regulation in brain and testis: common themes for highly specialized organs.
Expansion of the coding and regulatory capabilities of eukaryotic transcriptomes by alternative splicing represents one of the evolutionary forces underlying the increased structural complexity of metazoans. Brain and testes stand out as the organs that mostly exploit the potential of alternative splicing, thereby expressing the largest repertoire of splice variants. Herein, we will review organ-specific as well as common mechanisms underlying the high transcriptome complexity of these organs and discuss the impact exerted by this widespread alternative splicing regulation on the functionality and differentiation of brain and testicular cells.
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From Dysbiosis to Blood-Brain Barrier Disruption: The Metabolite-Mediated Gut-Brain Axis in Alzheimer's Disease.
Alzheimer's disease (AD) is not merely a central nervous system disorder; rather, it is a systemic condition profoundly influenced by the peripheral internal environment. Recent research has revealed that imbalances in the gut microbiota (GM) and metabolite disturbances contribute to AD onset and progression. Clinical and animal studies have indicated that AD patients commonly exhibit reduced GM diversity, decreased populations of short-chain fatty acid (SCFA)-producing and indole-producing bacteria, disrupted bile acid (BA) profiles, and elevated levels of trimethylamine N-oxide (TMAO) and kynurenine pathway (KP) activity. These alterations not only reflect gut dysbiosis, but also impair blood-brain barrier (BBB) integrity and amplify neuroinflammation by modulating tight junction proteins and inflammatory signaling through their effects on receptors and transporters such as G protein-coupled receptors(GPR41/43), aryl hydrocarbon receptor(AhR), Farnesoid X receptor(FXR)/ Takeda G protein-coupled receptor 5(TGR5), L-type amino acid transporter 1(LAT1), and Major Facilitator Superfamily Domain containing 2A(MFSD2A). From an integrative perspective, these changes -including short-Chain Fatty Acids (SCFAs) deficiency, elevated TMAO and toxic BA levels, overactivation of the KP, and Lipopolysaccharides (LPS) leakage-often act synergistically, collectively forming key pathological nodes in the "metabolic network-BBB-AD" axis. GM-targeted strategies such as dietary interventions, probiotics and fecal microbiota transplantation (FMT) have demonstrated potential in improving metabolite profiles and BBB homeostasis. Future research should utilize induced pluripotent stem cell-derived organoids and multi-omics integration approaches to elucidate the spatiotemporal dynamics of metabolites within the gut-brain axis (GBA), thereby laying the foundation for precise microbiome-based interventions in AD.
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Neuron-Targeted Exosomal Delivery of siRNA Against RIPK3 Slows Neurodegenerative Progression in Alzheimer's Disease.
A major challenge in RNA therapeutics for central nervous system disorders is the lack of delivery systems capable of crossing the blood-brain barrier (BBB) while achieving cell-type-specific targeting. Herein, we develop an engineered exosomal siRNA delivery platform for systemic, neuron-targeted RNA transport to the brain. The platform leverages exosomes derived from an immortalized mouse hippocampal neuronal cell line as a biomimetic and functionally privileged material source, enhancing neuronal uptake and intracellular delivery efficiency. Through surface functionalization with a rabies virus glycoprotein-derived peptide, the system enables receptor-mediated BBB transcytosis and programmable siRNA loading. In human cortical organoids, the platform achieves efficient cytosolic delivery and robust gene silencing in neurons, demonstrating high delivery precision and bioavailability. As a proof of concept, targeting receptor-interacting protein kinase 3 (RIPK3) modulates necroptosis, a key pathway in inflammatory neurodegeneration. In transgenic mouse models, systemic administration suppresses RIPK3/MLKL signaling, reduces neuronal loss, and alleviates neuroinflammation and tau-associated pathology. Transcriptomic analyses further indicate stabilization of neuronal homeostasis across vulnerable brain regions. Collectively, the study establishes a modular and programmable exosomal RNA delivery platform and highlights age-defined, cell-derived biomaterials as a generalizable strategy for overcoming delivery barriers in neurological diseases.
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Two translocation mechanisms drive neural stem cell dissemination into the human fetal cortex.
The strong increase in the size of the human neocortex is supported by a neural stem cell population, the basal radial glial (bRG) cells. Using live imaging of human fetal tissue and cortical organoids, we identify two translocation mechanisms for bRG cell colonization of the human neocortex. On top of an actomyosin-dependent movement called mitotic somal translocation (MST), we identify a microtubule-dependent motion occurring during interphase that we call interphasic somal translocation (IST). We show that IST is driven by the dynein motor and its activator LIS1, which are recruited to the nuclear envelope by the LINC complex, while MST is controlled by the mitotic cell-rounding pathway. Eighty-five percent of bRG cell translocation is due to IST, resulting in a total movement of 0.67 mm per month of gestation. Our work identifies how bRG cells colonize the human fetal cortex and further shows that IST and MST also occur in bRG-related glioblastoma cells.
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Characterization of a distinct form of vimentin in the neurodegenerative brain.
Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by brain accumulation of aggregated proteins, leading to neuronal and glial dysfunction. Compelling data indicate that changes in vimentin expression, structure, and localization reflect alterations in cellular homeostasis and may correlate with disease progression. Yet, the involvement of abnormal vimentin in AD and PD remains unclear. Here, we have thoroughly characterized the distribution of modified, disease-associated vimentin in the AD and PD brain parenchyma, as well as in cerebrospinal fluid (CSF), hiPSC-derived astrocytes and organoids. For this purpose, we used the form-specific vimentin antibody [84-1], originally generated to recognize abnormal vimentin on the surface of sarcoma cells. The 84-1 vimentin reactivity pattern was characterized through immunohistochemistry and proximity ligation assay. Moreover, proteomic analysis, Western blot, and ELISA were performed to quantify 84-1 vimentin levels and gain insights into its molecular features. Our data demonstrate that 84-1 can identify a distinct population of vimentin in the human brain that shows low affinity to commonly used vimentin antibodies. The 84-1 vimentin is enriched in disease conditions and forms distinct deposits in the affected regions of the AD and PD brain, often colocalizing with pathological protein aggregates. Interestingly, the 84-1 vimentin pool consists mainly of cleaved proteoforms and reduction-resistant aggregates. Moreover, 84-1 vimentin levels are elevated in the CSF of AD and PD patients as well as in the culture medium of human astrocytes exposed to αSyn or Aβ fibrils. Taken together, our data highlights the importance of modified vimentin in neurodegeneration and presents 84-1 vimentin as a potential biomarker and future treatment target for AD and PD.
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Toward a neurospheroid niche model: optimizing embedded 3D bioprinting for fabrication of neurospheroid brain-like co-culture constructs.
A crucial step in creating reliablein vitroplatforms for neural development and disorder studies is the reproduction of the multicellular three-dimensional (3D) brain microenvironment and the capturing of cell-cell interactions within the model. The power of self-organization of diverse cell types into brain spheroids could be harnessed to study mechanisms underlying brain development trajectory and diseases. A challenge of current 3D organoid and spheroid models grown in petri-dishes is the lack of control over cellular localization and diversity. To overcome this limitation, neural spheroids can be patterned into customizable 3D structures using microfabrication. We developed a 3D brain-like co-culture construct using embedded 3D bioprinting as a flexible solution for composing heterogenous neural populations with neurospheroids and glia. Specifically, neurospheroid-laden free-standing 3D structures were fabricated in an engineered astrocyte-laden support bath resembling a neural stem cell niche environment. A photo-crosslinkable bioink and a thermal-healing supporting bath were engineered to mimic the mechanical modulus of soft tissue while supporting the formation of self-organizing neurospheroids within elaborate 3D networks. Moreover, bioprinted neurospheroid-laden structures exhibited the capability to differentiate into neuronal cells. These brain-like co-cultures could provide a reproducible platform for modeling neurological diseases, neural regeneration, and drug development and repurposing.
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An epidermal nevus syndrome with cerebral involvement caused by a mosaic FGFR3 mutation.
A 5-year-old Mexican girl had a bilateral, systematized epidermal nevus of a non-epidermolytic, non-organoid type covering large parts of her body with the exception of the scalp. Clinically, this nevus was of a soft, velvety type showing affinity to the large body folds. Histopathological examination revealed orthohyperkeratosis and papillomatosis without granular degeneration and without any abnormality of adnexal structures. During infancy she developed seizures, and subsequently a delayed mental development was noted. Computer tomography of the brain revealed cortical and subcortical atrophy, a subdural hygroma in the left frontoparietotemporal region, and hypoplasia of corpus callosum. Molecular analysis of a biopsy specimen obtained from the epidermal nevus revealed a heterozygous R248C hotspot mutation in FGFR3, whereas in normal skin the FGFR3 wild-type allele was exclusively found. The R248C mutation was also present in DNA extracted from blood leukocytes. Because FGFR3 is involved in the development of the central nervous system, the clinical and genetic findings of this case indicate a widespread mosaicism of the FGFR3 mutation. This unusual mosaic phenotype may represent a distinct entity within the group of epidermal nevus syndromes.
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SARS-CoV-2 infection and viral fusogens cause neuronal and glial fusion that compromises neuronal activity.
Numerous viruses use specialized surface molecules called fusogens to enter host cells. Many of these viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can infect the brain and are associated with severe neurological symptoms through poorly understood mechanisms. We show that SARS-CoV-2 infection induces fusion between neurons and between neurons and glia in mouse and human brain organoids. We reveal that this is caused by the viral fusogen, as it is fully mimicked by the expression of the SARS-CoV-2 spike (S) protein or the unrelated fusogen p15 from the baboon orthoreovirus. We demonstrate that neuronal fusion is a progressive event, leads to the formation of multicellular syncytia, and causes the spread of large molecules and organelles. Last, using Ca2+ imaging, we show that fusion severely compromises neuronal activity. These results provide mechanistic insights into how SARS-CoV-2 and other viruses affect the nervous system, alter its function, and cause neuropathology.
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Molecular insights into glial neuroimmune cross reactivity with CNS antigens and its role in neuroinflammation.
Neuroinflammation has been increasingly considered a key player of neurodegenerative as well as psychiatric disorders. This review integrates existing knowledge on glial-neuroimmune interactions, emphasizing the roles of cytokine signaling, glial activation, and BBB modulation in neuro-pathogenesis. A systematic review was performed studying peer-reviewed literature on molecular pathways of microglia, astrocytes, endothelial cells, and peripheral immune mediators. A possible explanation of this finding could be that the model is based on the underlying pathophysiology, and this is shared across disease contexts, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury. Novel in vitro platforms, including the organ-on-a-chip and brain organoids, were also discussed for their translational potential. Microglia M1/M2 polarization and astrocyte reactivity appeared to be a common feature in neurotoxicity as well as excitotoxicity and chronic inflammation. Cytokine cascade of TNF-α, IL-1β, and IL-6 led to the disrupted BBB, allowing for peripheral immune cells to infiltrate. Both the NLRP3 inflammasome and mitochondrial dysfunction were identified as enhancers of neuroimmune signaling. Comparing across disease models, shared relationships emerged between glia-cytokines-BBB. Advanced in vitro systems proved to be useful to model these interactions and screen prescription drugs. This review highlights existing insights into glia-neuroimmune cross-reactivity and its critical role in CNS disease. The molecular interactions between these molecules could represent promising targets for novel therapeutic options. We suggests integrative systems platforms and AI-driven strategies to expedite clinical translation in neuroinflammation.
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Placenta-Brain Axis Under Heat Stress: Inflammatory Pathways Linking Prenatal Thermal Exposure to Offspring Neurodevelopment.
Climate change is increasing the frequency and intensity of extreme heat events, raising concern about prenatal thermal exposure as a potential risk factor for fetal brain development and offspring neurodevelopment. This systematic review aimed to synthesize evidence on prenatal heat exposure, placental inflammatory or stress-response pathways, and fetal or offspring neurodevelopmental outcomes, while evaluating the placenta-brain axis as a proposed mechanistic hypothesis rather than an established causal pathway. A systematic literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, Google Scholar, and Embase from database inception to 30 June 2026. Human observational studies, animal experiments, and in vitro mechanistic studies were included when they examined prenatal thermal exposure in relation to either placental function and stress-response mechanisms or fetal-brain and offspring neurodevelopmental outcomes. Ambient environmental heat, infectious fever, behavioral or exogenous heat exposure, experimental maternal hyperthermia, and direct cellular or organoid thermal stimulation were considered separately because these exposures are not biologically equivalent. Across the included studies, distinct prenatal thermal exposures-including ambient environmental heat, infectious fever, behavioral or exogenous heating, and experimentally induced hyperthermia-were associated with congenital central nervous system anomalies, including neural tube defects, as well as later outcomes such as neurodevelopmental delay, language impairment, autism spectrum disorder, cerebral palsy, and altered child-brain morphology. The strongest and most consistent early-pregnancy signal concerned neural tube defects during the periconceptional and neurulation periods, whereas evidence for later neurodevelopmental outcomes identified more heterogeneous susceptibility windows across gestation. Experimental evidence suggested alterations in placental barrier function, glucocorticoid and serotonin-related signaling, inflammatory and oxidative pathways, myelination, apoptosis, and neural-progenitor development. However, only one included experimental study jointly assessed maternal heat stress, placental alterations, and fetal-brain-related outcomes, while the human studies did not measure placental mediators or perform mediation analyses. Evidence from non-heat inflammatory studies therefore provides only indirect mechanistic context. Overall, prenatal heat exposure may contribute to neurodevelopmental vulnerability through multiple direct and indirect pathways, including a biologically plausible but unproven placenta-brain framework. Prospective studies integrating individual-level heat assessment, placental biomarkers, standardized fetal-brain imaging, and longitudinal neurodevelopmental follow-up are required to test this hypothesis.