Biology subjects

Sun, D.

Publications and source records attributed to Sun, D..

At least 19 recordsLinked to original sources

bioRxiv2026

Induced microfold cells are required for the function of pulmonary tertiary lymphoid organs that promote mucosal immunity

Tertiary lymphoid organs (TLOs) arise in response to infection and inflammation. We show that influenza-induced lung TLOs are comprised of inducible M cell (iM cell)-inducible bronchus-associated lymphoid tissue (iBALT) functional composites. iM cells are necessary for the appropriate architecture of adjacent immune follicles, which contain clonally expanded and sequence-diversified B cells. iM cell ablation results in fewer antigen-specific germinal center B cells, T follicular helper cells, and T helper memory cells, and a decrease in secretory IgA and IgG production accompanied by a loss of viral control. We find that the iM cells arise from epithelial progenitors that respond to a RANKL signal from infiltrating T cells, consistent with a model in which the patchy inflammation typical of pneumonia results in the unpredictable and varying distribution of coupled iM cells and adjacent iBALT. We propose that iM cells could be harnessed to promote infection control and enhance mucosal vaccination.

immunology↗

bioRxiv2026

Deep brain stimulation of the mesencephalic locomotor centre induces stimulation-dependent behavioural states beyond locomotion

Deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR) has been explored to treat gait disturbances. However, clinical outcomes of MLR-DBS have been disappointing overall, with only modest benefits in some individuals and unwanted effects, including anxiety, reported in others. Preclinical studies in several species, by contrast, show that MLR-DBS can improve locomotor and gait deficits, although defensive behaviours in response to stimulation have also been reported in some species. To investigate this discrepancy, we examined frequency- and amplitude-dependent effects of MLR-DBS in healthy rats, combining semi-supervised and unsupervised behavioural analyses. High-frequency, high-amplitude DBS (80-130 Hz), but not low-frequency stimulation (20-60 Hz), elicited hyperlocomotion intermixed with acute defensive-like behaviours. Low-frequency stimulation instead promoted phases of immobility. Consistently, only high-frequency DBS induced region-specific c-Fos expression in the MLR. Complex behaviours, including hyperlocomotion, rearing, tail rattling, and periods of immobility, were most pronounced in animals with the DBS electrode tip localized to the cuneiform nucleus (CnF) of the MLR. Using AAV tracer constructs for bright labelling of CaMKII-positive neurons and their axons, we identified prominent ascending projections from the CnF to the thalamus, substantia nigra pars compacta, zona incerta, hypothalamus, subthalamic nucleus, and central amygdala (CeA). Retrograde tracing confirmed the CnF-to-CeA projection independently. These findings show that the MLR is anatomically connected to higher-order centres linking motor and defensive networks, with DBS frequency and amplitude critically shaping behavioural outcomes that extend beyond locomotion.

neuroscience↗

bioRxiv2026

Rac1 and CHK1 Converge on Abi-1 to Regulate DNA Repair Dependency and Treatment Response in Human Cancers

Radiation therapy (RT) resistance remains a major clinical challenge, yet biomarkers guiding precision radiosensitization are lacking. We previously demonstrated that Rac1 promotes RT resistance in glioblastoma (GBM) by inducing Abi-1-S323 dephosphorylation and enhancing non-homologous end joining (NHEJ). Here, we identify Abi-1-S323 as a key regulator of DNA repair states and a determinant of therapeutic efficacy in human cancers. Clinically, loss of Abi-1-S323 phosphorylation was associated with poor outcomes in patients with RT-treated GBM. Bioinformatic analyses revealed that non-small cell lung cancer (NSCLC) and head and neck cancer (HNC) are among the cancers with frequent RAC1 amplification, suggesting that these tumor types may have increased Rac1-Abi-1 signaling activity. Loss of Abi-1-S323 phosphorylation also predicted poor outcomes in patients with RT-treated HNC. Consistent with these clinical observations, high Rac1 activity and low Abi-1-S323 phosphorylation were associated with enhanced DNA double-strand break repair and radioresistance in NSCLC and HNC models, whereas genetic or pharmacological inhibition of this signaling impaired DNA repair and radiosensitized tumors in vitro and in vivo. Mechanistically, we identified CHK1 as a kinase that phosphorylates Abi-1 at S323 and defines an alternative homologous recombination (HR)-dependent repair state. Tumors with high Rac1-Abi-1 signaling exhibited elevated NHEJ capacity and were selectively radiosensitized by Rac1 inhibition, whereas tumors with low Rac1-Abi-1 signaling displayed high CHK1 activity, preferentially relied on HR, and were selectively radiosensitized by CHK1 inhibition. These findings establish Abi-1-S323 as a biomarker defining therapeutically distinct DNA repair states and provide a framework for precision radiosensitization.

cancer biology↗

bioRxiv2026

A scalable human neuron model of Alzheimer's disease relevant tauopathy reveals mechanisms linking Tau fibrillization to synaptic dysfunction

Tauopathies, including Alzheimer's disease, are driven by pathological aggregation of hyperphosphorylated Tau, which disrupts synaptic integrity, impairs neuronal communication, and contributes to cognitive decline. To dissect tauopathy pathogenesis and enable therapeutic discovery, reliable and scalable human iPSC-neuron models are essential. Here, we developed two complementary iPSC-derived neuron models: an endogenous Tau seeding model, in which neurons are challenged with pre-formed Tau fragments that form paired helical filament (PHF)-consistent structures, and a Tau-0N3R overexpression seeding model to accelerate pathology. Both models recapitulate hallmark features of tauopathy, including the progressive formation of intracellular, hyperphosphorylated, sarkosyl-insoluble, and conformationally altered Tau aggregates (AT8, MC1 positive), along with synaptic and neuronal dysfunction. Cryogenic electron tomography (cryo-ET) further revealed the morphology of Tau fibrils within cells, as well as the ultrastructure of Tau fibrils trapping synaptic vesicles in situ. Using this platform, we performed integrated phosphoproteomics, high-content screening, and functional validation to identify key pathways driving Tau aggregation. MARK2-mediated phosphorylation within Tau's microtubule-binding domain emerged as an early trigger of aggregation, confirmed by site-specific mutagenesis. In parallel, small molecules targeting the PI3K/mTOR/GSK3 pathway reduced aggregation and restored synaptic function, with GSK3 inhibition lowering phosphorylation at critical aggregation-driving sites on Tau. Together, these findings establish a physiologically relevant, scalable platform for therapeutic screening that connects Tau seed uptake, site-specific phosphorylation, fibril formation, and synaptic disruption, ultimately identifying mechanistically separable intervention points along the aggregation cascade.

cell biology↗

bioRxiv2026

Blood-Mediated Opto-Acoustic Stimulation of Brain Cortex at Sub-millimeter Precision

Direct modulation of neural activity with high spatiotemporal precision is a cornerstone in experimental neuroscience. Here, we present a blood-mediated optoacoustic stimulation (BOAS) approach that utilizes blood as an endogenous transducer for brain stimulation. By delivering 532-nm nanosecond pulsed laser to the cortex, we demonstrate that the absorption of hemoglobin generates sufficient acoustic pressure to trigger neuronal activity. By integrating BOAS with calcium imaging in GCaMP6f-expressing mice, localized neuronal responses were observed. Quantitative analysis reveals that BOAS produces responses comparable to natural visual stimulation and is significantly more efficient than the photothermal stimulation. Furthermore, we show that the response is dose-dependent. At high energy doses, BOAS induces cortical spreading depression. Histological evaluation confirmed that the brain maintains tissue integrity even under these stimulation parameters. Together, this work establishes a versatile method for precise brain stimulation as an alternative method for stimulating neuron at cortex.

bioengineering↗

bioRxiv2026

Characterizing benthic community structure across Western Pacific seamounts to ~5,000 m depth: Implications for conservation

AimSeamounts are key components of deep-sea ecosystems. Yet, their biodiversity patterns and conservation needs remain poorly understood, presenting a critical knowledge gap as they face multiple environmental stressors. Here, we aim to characterize benthic community structure across multiple seamounts along the Kyushu-Palau Ridge (KPR) and identify conservation priorities. LocationPhilippine Sea in the Western Pacific. Major taxa studiedDeep-sea benthos. MethodsWe surveyed six transects (13.3{degrees}N-22.9{degrees}N; 614-5,055 m depth; 165 kilometers in total length) using a towed camera system, yielding 31,342 images and 14,218 identified individuals. Community structure was assessed through species depth-range overlap analysis to distinguish nestedness versus turnover patterns. {beta}-diversity was partitioned into local contributions (LCBD) and species contributions (SCBD) to evaluate site-level uniqueness and species-level influence. Generalized linear mixed models were used to relate LCBD and SCBD to depth, slope, aspect, bathymetric position, and functional traits. ResultsCommunity structures varied among slopes and seamounts. Western, steeper slopes were dominated by nestedness, whereas gentler eastern slopes showed mixed patterns of nestedness and gradual turnover. Sessile species largely exhibited nestedness, while mobile taxa showed mixed structures. LCBD declined with depth overall but increased on north-facing slopes and sites with higher broad-scale bathymetric position. Wide-ranging generalist species, particularly among Echinoidea and Holothuroidea, contributed disproportionately to {beta}-diversity. Main conclusionsSeamount benthic communities along the KPR are structured by interactions between depth, geomorphology, and species ecological breadth. The dominance of nestedness on western slopes suggests that protecting shallow, species-rich habitats could capture much of the biodiversity therein. In contrast, the mixed structures on eastern slopes indicate the need for a hybrid conservation approach that includes both shallow summits and deeper, compositionally distinct zones. Our findings highlight the importance of slope-specific, depth-informed strategies to conserve these vulnerable marine ecosystems.

ecology↗

bioRxiv2026

Hidden genetic diversity in 320 nearly-complete East Asian genome assemblies

East Asian populations, representing over 20% of the global population, remain critically underrepresented in human genomic studies, limiting our understanding of population-stratified genetic variation and its implications for health and disease. Here we present the first phase of the Asian Pan-Genome project (APG), comprising 320 nearly complete, fully phased haploid genome assemblies from 160 East Asian individuals. These assemblies achieve unprecedented quality, with an average contig N50 of 144.3 megabase pairs and an average quality value of 64.5. Leveraging these superior assemblies, we reveal previously uncharacterized diversity in human repeatome, including population-stratified patterns in centromere satellites and rDNA arrays. Compared to existing global human genome assemblies, the newly generated genomes supplement 152 million base pairs of novel sequences, 355 gene gains, 18,300 structural variation loci and 26 large euchromatic inversions missing from current human pangenomes. We perform population stratification analyses of structural variations, and further resolve the structural haplotypes of complex genomic regions such as Major Histocompatibility Complex and Survival Motor Neuron loci across global pangenomes, exemplifying tandem-duplicate and inversion-rich complex locus architectures in the human genome, respectively. This resource provides a critical foundation for human genetic studies, especially for East Asian populations, promoting more accurate variant discovery, reducing bias, and ultimately advancing the equity and efficacy of genomic medicine.

genomics↗

bioRxiv2026

Multivalent Tau-Fyn interactions cooperatively arrest postsynaptic density condensate dynamics

Tau-Fyn signaling at postsynaptic sites is implicated in synaptic dysfunction and neuronal hyperexcitability in Alzheimers disease and related tauopathies, yet the molecular mechanisms by which Tau-Fyn interactions influence postsynaptic signaling assemblies remain poorly understood. Here, we reconstitute biomolecular condensates and membrane-associated assemblies that mimic the postsynaptic density (PSD) to investigate how Tau and Fyn regulate PSD organization and dynamics. We show that Tau and Fyn co-partition into PSD condensates and N-methyl D-aspartate receptor subtype 2B (NR2B)-associated PSD clusters, with both proteins preferentially enriching in the condensed phase relative to core PSD scaffold proteins. Enrichment of Fyn within PSD condensates is recapitulated by an SH3-SH2 fragment lacking the kinase domain, indicating that the kinase domain is dispensable for condensate partitioning. Fluorescence recovery after photobleaching reveals that Tau markedly reduces Fyn mobility and, together with Fyn, cooperatively drives a pronounced dynamic arrest of PSD condensate components, including the central scaffold protein PSD-95. Disruption of a major Tau-Fyn interaction hotspot by P216A/P219A mutations in Tau nearly completely restores the mobility of both Fyn and PSD-95, demonstrating that cooperative Tau-Fyn interactions are required for dynamic arrest. NMR spectroscopy identifies a multivalent interaction network between the Tau proline-rich region and the Fyn SH3 domain involving multiple binding motifs, with residues P216 and P219 acting as major interaction determinants. A 1.4 [A] crystal structure of the Fyn SH3 domain bound to a Tau peptide reveals a ternary 2:1 Fyn:Tau assembly, providing structural support for multivalent Tau- Fyn engagement. Together, our findings establish a condensate-based mechanism by which multivalent Tau-Fyn interactions cooperatively regulate PSD condensate dynamics and provide a molecular framework linking Tau-Fyn signaling to synaptic dysfunction in tauopathies.

biochemistry↗

bioRxiv2026

Dissociable Neural Responses to Conditioned Social Threats are Modulated by Spatial Proximity in PTSD and MDD

The brains response to potential threats is shaped by the egocentric spatiotemporal distance to the threat. While distal threats recruit evaluative, cognitive-fear networks for strategic planning, proximal threats engage evolutionarily conserved reactive-fear circuitry to mount immediate defensive responses. Understanding this dual neural architecture is clinically relevant, as the spatial proximity to a traumatic event predicts subsequent psychiatric symptom severity and recovery. Despite the well-characterized disruptions to threat circuitry in posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), how these networks respond to threats at distinct spatial distances has yet to be investigated in these disorders. Utilizing 3D virtual reality technology, we implemented a spatially-modulated fear conditioning paradigm by presenting human avatars at proximal (peripersonal) and distal (extrapersonal) distances, paired with shock, to trauma-exposed participants (n = 50) during functional MRI (fMRI). We modeled associations between PTSD and MDD symptom severity and task-evoked hemodynamic responses within cognitive-fear and reactive-fear threat networks. Our results support a transdiagnostic disruption of thalamic responses to proximal threats, driven by heightened activation to the safety stimulus and stronger deactivation to the threat stimulus. MDD showed a disorder-specific effect of disrupted activity across cognitive-fear and social cognition regions in response to proximal social threats, and illness severity-by-proximity effects across motor regions. PTSD symptom severity was uniquely associated with hyperactivity of the amygdala to distal threats. Transdiagnostic disruption of connectivity between the dorsal precuneus and several subcortical structures followed a disorder-specific gradient across the anterior-posterior axis. While thalamic disruptions to threats represent a shared transdiagnostic effect, PTSD and MDD are distinguished by differences in amygdala hyperactivation and cognitive-fear network hypoactivation, respectively.

neuroscience↗

bioRxiv2026

Type I interferon primes the alveolar epithelium to receive reparative signals from tissue-resident macrophages

Lung repair in response to viral infection requires integrated communication between epithelial and immune compartments, yet the impact of antiviral mediators on epithelial regenerative capacity remains poorly defined. Here, we demonstrate that type I interferon (IFN-I) signaling primes the lung for alveolar renewal following viral challenge. IFN-I contributes to the induction of an interferon-stimulated gene-high (ISG)hi Sca-1Pos population of alveolar type II (ATII) epithelial cells. Sca-1Pos ATIIs exhibit enhanced proliferative capacity and increased organoid-forming efficiency compared with their Sca-1Neg counterparts. Viral challenge concurrently drives phenotypic reprogramming of tissueresident alveolar macrophages (trAMs). Sca-1Pos ATIIs display heightened responsiveness to oncostatin M (OSM) and, following viral challenge, require trAM-derived OSM for their proliferation. Together, these findings reveal that viral stimuli induce coordinated IFN-I-dependent epithelial and macrophage states that poise the lung for regeneration, positioning IFN-I not only as a central antiviral defense mechanism but as a priming signal that prepares lung tissue for renewal.

immunology↗

bioRxiv2026

Long-read RNA-seq resolves isoform-level and context-specific regulatory architecture of complex traits in cattle

Traditional short-read RNA-seq lacks the resolution to fully capture full-length isoforms and complex alternative splicing, leaving a "missing regulation" gap in existing molecular atlases. Here, we present a population-scale, multi-omics dissection of bovine complex traits using matched deep whole-genome sequencing (30x), long-read (ONT) and short-read RNA-seq, as well as metabolome data from 432 dairy cows across four distinct lactation stages. We expanded the bovine transcript atlas with 13,177 novel isoforms and fine-mapped 1,088,900 regulatory effects across 11 diverse molecular phenotypes. Notably, long-read mapping uncovered 606 genes with isoform expression quantitative trait loci (12.8%, eQTL) and 1,116 genes with detailed splicing QTL (sQTL) (31.8%) that were missed by conventional short-read mapping. We further showed that lactation-specific regulation was profoundly mediated by the metabolic microenvironment (46.8%) and cellular composition (4.3%). Across genome-wide associations (GWAS) of 90 bovine complex traits, isoform-level and context-specific regulatory effects captured GWAS loci missed by short-read eQTL and sQTL analyses, increasing colocalized loci from 35.2% to 60.3%. These regulatory variants also exhibited evolutionary constraints with human immune and metabolic loci. Our study establishes an invaluable resource (https://cattleblr.farmgtex.org) demonstrating that long-read transcriptomics is essential for resolving the complexity of regulatory mechanisms underlying mammalian physiology.

genetics↗

bioRxiv2026

Transcription initiation profiling defines the regulatory logic of astrocyte gene regulation

Astrocytes are central regulators of neuroinflammation, yet the mechanisms by which they convert common inflammatory signals into cell type-specific transcriptional responses remain poorly understood. Here we mapped transcription initiation genome-wide in primary mouse astrocytes stimulated with interleukin-1B (IL-1B) and defined the active regulatory elements that drive astrocyte reactivity. We find that inducible enhancer transcription in astrocytes is encoded by a transcription-initiation grammar in which lineage-restricted transcription factors, particularly NFIA and TEAD4, cooperate with inflammatory transcription factors such as NF-{kappa}B, AP-1 and IRF to drive stimulus-dependent transcription activation. The motifs of these inflammatory transcription factors show a strong positional bias upstream of induced transcription start sites, supporting their direct role in controlling initiation upon stimulation. Moreover, NF-{kappa}B and TEAD4 motifs are preferentially associated with sites showing altered patterns of transcription initiation in response to inflammatory stimulus. Comparison with stimulated macrophages revealed that, despite substantial overlap in induced genes, astrocytes exhibit a largely distinct enhancer repertoire, indicating that shared inflammatory signals are interpreted through cell type-specific regulatory landscapes. Finally, transcribed astrocyte regulatory elements are functionally conserved in human astrocytes and are enriched for genetic risk variants associated with neurological disorders. Together, these findings define a cell type-specific regulatory logic for astrocyte inflammatory responses and link astrocyte enhancer regulation to human disease susceptibility.

genomics↗

bioRxiv2026

Reveal Principles of Codon Optimization via Machine Learning

High level of protein expression is usually welcomed in industry and research, and codon optimization is widely used to achieve high expression. Methods of implementing codon optimization can be divided into two branches, one is classical methods which develop cost functions based on empirical law, another is AI methods which learn the codon choice principles from endogenous genes with neural networks. Here we develop two codon optimization tools based on two branches respectively, namely OptimWiz 2.1 and OptimWiz 3.0. Results of fusion protein fluorescence detection indicate that both OptimWiz 2.1 and OptimWiz 3.0 are superior to all the other commercially available codon optimization tools. Principles of codon optimization are revealed in the process of machine learning on both tools.

bioinformatics↗

bioRxiv2026

SPEND-hSRS imaging of fumarate uncovers mitochondrial metabolic heterogeneity

Mitochondria, acting as the energy powerhouse, biosynthetic center, and reductive equivalent hub of the cell, participate in cellular metabolic activities. However directly imaging mitochondrial chemical content and quantifying metabolic activity in living cells remain challenging. Here, by Self-PErmutation Noise2noise Denoiser enhanced Hyperspectral Stimulated Raman Scattering (SPEND-hSRS) microscopy, we demonstrate fingerprint-region metabolic imaging of fumarate, a key intermediate in the tricarboxylic acid (TCA) cycle, with sub-millimolar sensitivity. In chemotherapy-stressed bladder cancer cells, fumarate imaging revealed two mitochondrial subpopulations with divergent TCA metabolic preferences quantified by ratio metric analysis. Pixel-wise least absolute shrinkage and selection operator (LASSO) spectral unmixing further reconstructs fumarate and lipid maps, uncovering localized fumarate enrichment in protrusions. Extending to CH-window hyperspectral SRS imaging, we uncover the interplay between mitochondria and lipid droplets (LDs) in protrusions, where fatty acid is found to be released from LDs, to fuel the TCA cycle. Together, our work establishes SPEND-hSRS as high-resolution platform for linking fumarate to mitochondrial heterogeneity. Our results provide new insights into how mitochondrial heterogeneity and interaction with LDs drive cancer cell adaptation to stress.

cancer biology↗

bioRxiv2026

In vivo interrogation of transcriptional and epigenetic regulators of lung epithelial regeneration

Effective alveolar repair after viral lung injury requires precise coordination of alveolar type 2 cell (AT2) proliferation and differentiation to restore lung function. To uncover causal regulators of this process in the native tissue environment, we developed SAGE (Stable Adeno-Associated Virus Genomic IntEgration), an engineered AAV system that enables high-throughput in vivo genetic interrogation. SAGE supports both bulk phenotypic screening (SAGE-Perturb) and single-cell transcriptomic profiling (SAGE-Perturb-seq). Using this approach, we identified lysine acetyltransferase 8 (Kat8) as essential for epithelial repair following viral infection through the Non-Specific-Lethal (NSL) complex, and generated a time-resolved, high-resolution functional map of transcription factor knockouts during alveolar repair, revealing transcription factor dependences for distinct alveolar epithelial repair trajectories. This map further defined two independent AT2-derived transitional states: a reparative state, and a pathological state that is transcriptionally similar to the basaloid population observed in human pulmonary fibrosis. Disruption of transcription factors in the NF-{kappa}B pathway prevented the emergence of the pathological transitional state, linking inflammation and maladaptive epithelial remodeling. SAGE represents a versatile platform for functional genomics in vivo, with applications extending across respiratory biology and disease.

genomics↗

bioRxiv2026

Biodegradable Intra-arterial Devices for Focal Drug Delivery to Targeted Organs

This study presents the development of biodegradable intra-arterial drug delivery (IADD) devices for the focal treatment of targeted organs. The IADD devices are fabricated using magnesium (Mg) and poly(glycerol sebacate) (PGS), leveraging their biocompatibility and tunable biodegradability, and are loaded with two model drugs, dexamethasone (DEX) or cisplatin (CIS). The IADD devices with helical and linear designs were fabricated for focal drug delivery to targeted organs and characterized for their microstructure and composition using scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA), and Fourier-transform infrared spectroscopy (FTIR). The results confirmed the successful incorporation and stability of the drugs within the device. The IADD devices demonstrated in vitro release of DEX and CIS over 30 days, with drug-dependent and fabrication-dependent release profiles. The IADD devices demonstrated cytocompatibility with endothelial cells and sustained pharmacological activity against glioma cells throughout the in vitro release period. DEX-loaded IADD devices were implanted into the artery upstream of a target organ in rat models. The devices implanted into the renal artery to target the kidney and the carotid artery to target the brain achieved 109-fold and 68-fold improvements, respectively, in organ vs systemic drug levels compared to oral drug administration. Arterial histology and explanted-device analysis provided preliminary evidence of local vascular tolerability and device integrity over the examined implantation period. Overall, these results support IADD devices as a proof-of-concept approach for focal intra-arterial drug delivery to targeted organs, demonstrating substantially elevated target-organ drug levels relative to systemic exposure. HighlightsO_LIIntroduction of a novel intra-arterial drug delivery (IADD) platform C_LIO_LIIADD devices were fabricated from bioresorbable Mg and drug-loaded PGS C_LIO_LIDEX- and CIS-loaded IADD devices were evaluated for in vitro release and bioactivity C_LIO_LIIADD delivery achieved marked DEX enrichment in the kidney and brain C_LIO_LIPost-implantation studies support preliminary vascular safety C_LI

bioengineering↗

bioRxiv2026

Deletion of NLRP3 gene blocks traumatic brain injury induced abnormal immune response in 3xTg AD mice

Traumatic brain injury (TBI) is a significant risk factor for the development of Alzheimers disease (AD) and related dementia. In both TBI and AD, inflammation plays a pivotal role. It is known that NLRP3 inflammasome plays an important role in pathogenesis of AD while TBI triggers activation of NLRP3 inflammasome in the brain. To evaluate the importance of NLRP3 inflammasome in mediating TBI-induced immune response in the context of predisposition of AD, we have examined the immune profiles in the brain using a novel transgenic AD mouse line with the NLRP3 gene deleted. Briefly, a group of 4 months old male and female 3xTg and 3xTg/NLRP3-/- mice received a moderate lateral fluid percussive injury or sham. Immune cell phenotypes and cytokine gene expression were assessed at 3- and 7-days post injury (dpi). We found that NLRP3 gene deletion counteracted injury-induced alteration of immune response in AD mice with a significant sex-related difference. Specifically, TBI induced a significant brain infiltration of neutrophils, macrophages and {gamma}{delta} T-cells in 3xTg mice in both sexes at 3dpi, and NLRP3 gene deletion blocked this injury effect only in males not in females. NLRP3 gene deletion also blocked injury-enhanced IL-1{beta}, TNF- gene expression in male AD mice, but not in female mice. In conclusion, our study has confirmed that TBI significantly alters the immune response in 3xTg-AD mice and NLRP3 inflammasome is important in mediating these TBI-induced changes with significant sex-related differences.

immunology↗

bioRxiv2026

Traumatic brain injury has a lasting impact on hippocampal neurogenesis and Notch1 is involved in regulating this injury response

Traumatic brain injury (TBI) induces a series of neuropathological changes in the brain including neurogenesis, an important cellular response involved in brain repair and regeneration. TBI-enhanced neurogenesis in the dentate gyrus (DG) of the hippocampus is of particular importance due its contribution to learning and memory functions. In the neurogenic process, proliferation and differentiation of neural stem cells (NSCs) follow a well-characterized sequence controlled by many factors including Notch1, which plays essential roles in regulating NSC fate determination under physiological conditions in both developing and adult brains. Following TBI, the dynamic changes of NSCs and the involvement of Notch1 on their development at different stages post-injury are not fully characterized. In the current study, we examined the impact of TBI and Notch1 on NSCs proliferation, survival and neuronal differentiation. Utilizing transgenic mice with tamoxifen-induced GFP expression and Notch1 knock-out in nestin+ NSCs, we examined DG neurogenic response at acute, subacute and chronic stages following a moderate lateral fluid percussion injury. We found that TBI enhanced a proliferative response in the DG at the acute stage following injury; however, this injury response was abolished when Notch1 was conditionally deleted from nestin+ NSCs. We also found that injury and Notch1 deletion drove NSCs committing fate choice towards neuronal differentiation. The results of this study provides further knowledge regarding TBI-induced neurogenic response and Notch1 as the key regulating mechanism.

neuroscience↗