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Results for “pathology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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14 recordsLinked to original sources

bioRxiv2026

Multidimensional diffusion MRI reveals heterogeneous microstructural remodeling associated with amyloid pathology

Alzheimer's disease (AD) pathology involves amyloid deposition, reactive gliosis, and localized tissue alterations that coexist within the same brain regions, creating heterogeneous microstructural environments within individual imaging voxels. Conventional diffusion MRI averages these environments into aggregate measures, potentially obscuring their distinct contributions. Frequency-dependent multidimensional MRI ({omega}MD-MRI) resolves distributions of water components with different diffusion length scales, anisotropies, and relaxation properties, providing sensitivity to microstructural restriction, heterogeneity, and shape-size correlations within a voxel. Whether these measurements reveal microstructural complexity associated with AD pathology remains unclear. Here, we performed {omega}MD-MRI on ex vivo brain specimens from approximately 8-month-old 5xFAD and wild-type mice and interpreted the imaging findings alongside complementary histology. {omega}MD-MRI revealed widespread but spatially nonuniform differences between 5xFAD and wild-type brains. Measurements sensitive to microstructural restriction, heterogeneity, and shape-size correlations consistently indicated greater microstructural heterogeneity in 5xFAD brains, with the most prominent differences in the hippocampal formation and major cerebral white matter tracts. Complementary qualitative histology demonstrated extensive amyloid deposition and glial activation in affected regions, while overall cytoarchitecture and myelin organization remained largely preserved. Thus, the {omega}MD-MRI abnormalities occurred in tissue characterized by multiple coexisting pathological and relatively preserved microstructural environments rather than widespread structural degeneration. These findings demonstrate that {omega}MD-MRI can reveal the spatial and microstructural heterogeneity associated with amyloid pathology and provide a more comprehensive characterization of AD-related tissue alterations.

neuroscience↗

bioRxiv2026

Schizophrenia-like neurodevelopmental pathology reshapes experience-dependent brain network remodeling following adolescent alcohol exposure

Background Alcohol use disorder (AUD) is highly prevalent in schizophrenia, yet the neurobiological basis of this vulnerability remains poorly understood. Neurodevelopmental models suggest that pre-existing brain dysconnectivity may increase vulnerability to AUD. We therefore tested whether schizophrenia-like neurodevelopmental pathology alters how alcohol-related experience is incorporated into large-scale brain networks. Methods Resting-state functional connectivity was assessed in male Sprague-Dawley rats (n = 18-21/group) with neonatal ventral hippocampal lesions (NVHL), a neurodevelopmental model of schizophrenia, and sham-operated controls, with or without voluntary adolescent alcohol exposure. Functional connectivity was assessed using seed-to-voxel and seed-to-seed analyses within a cortico-striato-limbic network. We additionally examined whether individual alcohol intake during adolescence predicted adult functional connectivity according to neurodevelopmental status. Results NVHL and adolescent alcohol exposure independently produced predominantly hypoconnected cortico-striato-limbic networks. However, alcohol exposure did not exacerbate NVHL-associated dysconnectivity but instead induced a distinct network reorganization characterized by functional hyperconnectivity. Although alcohol intake was comparable between groups, dose-dependent relationships between adolescent alcohol consumption and adult functional connectivity were observed in sham animals but were absent or markedly attenuated in NVHL rats. These effects were primarily centered on prelimbic cortex connectivity with the amygdala, hippocampus, and dorsal striatum, highlighting this circuitry as a major locus of altered experience-dependent remodeling. Conclusions These findings suggest that vulnerability to AUD associated with schizophrenia-like neurodevelopment may arise less from additive network dysfunction than from an altered capacity of large-scale brain networks for experience-dependent functional remodeling. Schizophrenia-like neurodevelopmental pathology may therefore change how alcohol-related experience is translated into persistent brain network organization.

neuroscience↗

bioRxiv2026

NAE1-Dependent Protein Neddylation Preserves Endothelial Identity and Vascular Integrity

Background: Endothelial dysfunction is a central driver of cardiovascular and inflammatory diseases, yet the post-translational mechanisms that preserve endothelial homeostasis remain incompletely understood. Protein neddylation, the covalent conjugation of a ubiquitin-like modifier, regulates diverse cellular processes, yet its physiological role in the vascular endothelium remains unknown. This study investigated whether protein neddylation is required to preserve endothelial identity and vascular homeostasis. Methods: We generated tamoxifen-inducible endothelial-specific Nae1 knockout mice to inhibit neddylation and combined bulk RNA sequencing, single-cell and single-nucleus transcriptomics, quantitative proteomics, biochemical analyses, and gain- and loss-of-function approaches to define the role of endothelial neddylation in vascular homeostasis and inflammatory injury. Results: Endothelial-specific Nae1 deletion caused rapid mortality associated with vascular leakage, platelet accumulation, inflammation, and multi-organ injury. Multi-omics analyses demonstrated profound loss of endothelial identity, characterized by suppression of core endothelial programs and activation of inflammatory, procoagulant, and pyroptotic pathways. Single-cell analyses revealed progressive endothelial dysfunction culminating in depletion of the endothelial population and remodeling of the vascular niche. Mechanistically, endothelial neddylation deficiency activated gasdermin D (GSDMD)- and gasdermin E (GSDME)-dependent pyroptosis, whereas dual inhibition of GSDMD and GSDME markedly attenuated inflammatory transcriptomic remodeling, vascular injury, hepatocyte death, immune cell infiltration, and platelet accumulation. Translational analyses demonstrated reduced endothelial neddylation in experimental endotoxemia and decreased expression of neddylation pathway components in human atherosclerosis and COVID-19 datasets. Conversely, restoration of endothelial neddylation partially reversed inflammatory endothelial transcriptomic reprogramming in vivo. Conclusions: NAE1-dependent protein neddylation is an essential regulator of endothelial identity and vascular integrity. Loss of endothelial neddylation promotes gasdermin-dependent pyroptosis and thrombo-inflammatory vascular injury, whereas restoration of the neddylation pathway mitigates inflammatory endothelial dysfunction. These findings identify endothelial neddylation as a fundamental mechanism maintaining vascular homeostasis and a potential therapeutic target for cardiovascular and inflammatory diseases.

pathology↗

bioRxiv2026

Sensory neuron dysfunction and hyperexcitability in dorsal root ganglia at disease onset in the SOD1G93A mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder traditionally characterized by motor neuron degeneration, but emerging evidence indicates sensory system involvement. Despite reports of sensory abnormalities in some patients, the molecular and functional alterations in dorsal root ganglion (DRG) neurons remain insufficiently characterized. We investigated DRG pathology at disease onset in 12-week-old SOD1G93A mice using an integrated transcriptomic, morphological, and electrophysiological approach. RNA sequencing of lumbar DRG identified 35 differentially expressed genes, predominantly upregulated, enriched in oxidative stress-related and phagosome pathways. Comparative analysis with motor neuron transcriptomes revealed distinct gene expression profiles, indicating sensory neuron-specific molecular responses. Immunohistochemistry demonstrated reduced soma diameter in both A- and C-fiber DRG neurons. Nav channel colocalization increased for Nav1.7 in A fibers and Nav1.8 in both fiber types, whereas Nav1.6 was unchanged. Whole-cell patch-clamp recordings showed depolarized resting membrane potential, increased spike amplitude, and enhanced repetitive firing in A-fiber neurons, consistent with hyperexcitability, while C fibers showed no significant functional changes. These findings demonstrate early molecular, structural, and functional alterations in primary sensory neurons in ALS, supporting pathology beyond motor neurons and identifying sensory neuron excitability as a potential therapeutic target.

neuroscience↗

bioRxiv2026

Dysregulated splenic glucocorticoid sensitivity in aging and an α-synuclein transgenic mouse model of Parkinson's disease

Introduction: Parkinson's disease (PD) and aging both disrupt hypothalamic-pituitary-adrenal (HPA) axis function and peripheral immune homeostasis. Whether aging or -synuclein (-syn) pathology alters glucocorticoid (GC) sensitivity of peripheral immune cells has not been investigated. Methods: Using an ex vivo GC sensitivity assay, we assessed the responsiveness of isolated and lipopolysaccharide (LPS)-stimulated splenocytes to the anti-inflammatory effects of increasing doses of corticosterone (CORT) in a wild-type (WT) aging cohort and in a PD -syn transgenic mouse model and respective age-matched controls. Results: Compared with splenocytes from 6-month-old WT mice, splenocytes from 20-month-old WT mice were less sensitive to 0.1 and 0.5 M CORT. Isolated splenocytes from PD vs. control mice were less sensitive to 0.05, 0.1, and 0.5 M CORT specifically at 16 months of age, but not at 6 or 20 months of age. As peripheral immune phenotyping revealed neither differences in HPA axis-related parameters nor in splenic GC receptor expression between PD and age-matched control mice at 6, 16, and 20 months, splenic GC resistance in PD mice at 16 months of age seems to be mediated by downstream GR signaling dysfunction. Conclusion: Together, our results support the hypothesis that -syn pathology accelerates an aging-associated decline in the peripheral sensitivity to anti-inflammatory GCs and may thereby sustain systemic and neuroinflammatory processes in PD.

neuroscience↗

bioRxiv2026

MAPT regulates autophagic-lysosomal function and phagocytosis in human microglia

Tauopathies are characterized by the accumulation and spread of pathogenic tau aggregates throughout the brain, a process that is increasingly recognized to involve not only neurons but also microglia. However, whether pathogenic MAPT directly alters microglial degradative capacity remains poorly understood. Here, using isogenic human induced pluripotent stem cell-derived microglia carrying the pathogenic MAPT IVS10+16 mutation, we identify tau as a regulator of microglial lysosomal function. MAPT IVS10+16 microglia exhibited coordinated suppression of lysosomal and autophagic pathways, reduced lysosomal protease abundance and activity, and impaired autophagosome-lysosome fusion. Mutant microglia also showed reduced uptake of extracellular tau aggregates, reduced tau accumulation in acidic compartments, and a blunted lysosomal response to proteopathic stress. Conversely, genetic loss of MAPT increased lysosomal degradative capacity and accumulation of extracellular tau aggregates within acidic compartments, supporting a cell-intrinsic role for endogenous tau in regulating microglial degradative function. Pharmacologic enhancement of the autophagy lysosome pathway in MAPT IVS10+16 microglia increased proteolytic activity and improved tau handling. Together, these findings reveal a reciprocal relationship between tau and microglial lysosome function and identify degradative capacity as a modifiable component of the microglial response to tau pathology.

neuroscience↗

bioRxiv2026

m1A58 acts as a conformational checkpoint coupling human initiator tRNA maturation to translation initiation

tRNAs are characterized by extensive chemical modifications that influence tRNA fate. N1-methyladenosine at position 58 (m1A58) is a widespread core tRNA modification linked to physiological and pathological processes. However, how m1A58 coordinate tRNA folding and processing to ensure translational efficiency in mammalian cells remains largely unknown. Using acute dTAG-mediated degradation and CRISPR-Cas9 knockout, we identified initiator methionine tRNA (tRNAiMet) as selectively vulnerable to m1A58 loss, lacking the isodecoder buffering observed for most other tRNA isoacceptors. NMR analysis of the tRNAiMet showed that m1A58 stabilizes D/T-loop interactions, consistent with a maturation-competent conformation. In vitro processing assays further demonstrated that m1A58 promotes RNase P-mediated 5'-leader removal and RNase Z-mediated 3'-trailer cleavage, while La/SSB protects accumulated precursors. Disrupting this checkpoint impaired the assembly of the eIF2-containing 43S pre-initiation complex and global protein synthesis, which was substantially rescued by adding m1A58-modified tRNAiMet. Acute TRMT6 degradation elicited temporally coordinated gene-expression responses involving proteostasis, transport and signaling. Together, these findings establish m1A58 as a conformational checkpoint coupling human initiator-tRNA maturation to translation initiation and stress responses.

molecular biology↗

bioRxiv2026

Function-driven geometry directs human pilosebaceous unit development

Single-cell technologies have generated cell censuses of tissues, however, how tissue geometry reflects functional needs remains poorly characterized. The human pilosebaceous unit offers a tractable model, a prenatally-formed complex mini-organ combining hair and sebum production with a stem cell reservoir. Using histomorphology, spatial transcriptomics, and single-cell multiomics on the same human prenatal scalp skin samples (8-19 post-conception weeks), integrated and analyzed using machine learning approaches, we built a spatiotemporal map of pilosebaceous unit development. We demonstrate that epithelial-mesenchymal interactions coordinate cellular fate and organogenesis, using an in vitro hair-bearing skin organoid model to validate this tissue-patterning. In addition, we show sebaceous gland developmental programmes are overcome during tumor formation. Our large-scale multi-modal analysis provides a unique framework for understanding form and function of tissues with applications in tissue engineering and pathology.

developmental biology↗

bioRxiv2026

A Metabolic Labeling Strategy for Tracking Protein Synthesis in Complex Biological Systems

Protein synthesis supports most biological processes. In the brain in particular, protein synthesis plays a critical role in physiological and pathological states. Here, we describe Tellurophene-Alkyne Cycloaddition-mediated Amino acid Tagging (TeACAT), a versatile strategy for fast, facile, and flexible tagging of newly synthesized proteins in mice. TeACAT is based on metabolic incorporation of the non-canonical amino acid TePhe into proteins by the endogenous protein synthesis machinery. Due to their high similarity, TePhe can efficiently replace canonical Phe without dietary or genetic manipulation. The subsequent bio-orthogonal reaction of TePhe with either fluorescent dyes or affinity handles enables both visualization and affinity enrichment of proteins synthesized during TePhe exposure. TeACAT is compatible with immunofluorescence for cell-type specific visualization of protein synthesis with subcellular resolution and can be used in conjunction with routine proteomics to identify and quantify newly synthesized proteins. Robust incorporation into the mouse proteome was observed on the scale of hours to days, allowing the interrogation of various biological processes. In summary, TeACAT enables the visualization and quantification of protein synthesis with minimal perturbation for biological discoveries.

molecular biology↗

bioRxiv2026

Microglia drive demyelination via multiple sclerosis antibodies and BTK signaling

Microglia are the predominant immune cells in multiple sclerosis (MS) demyelinating lesions, where they phagocytose myelin, but whether they destroy myelin or merely scavenge its debris is unknown. Here, we explore whether pathogenic autoantibodies found in MS may induce the phagocytic destruction of myelin by microglia. Applying patient-derived, myelin-targeting antibodies to the mouse cortex, we developed an in vivo model of MS with focal demyelination that depended on epitope specificity and Fc gamma receptor and complement binding. Longitudinal monitoring of microglia-myelin interactions using in vivo two-photon microscopy revealed rapid microglial envelopment of intact myelin driving myelin loss, while single-cell RNA sequencing identified a demyelination-associated microglial signature. Parallel changes were observed in human MS lesions, where microglia enveloped intact myelin and similar genes were upregulated. Inhibition of Brutons tyrosine kinase (BTK) limited microglial transcriptional changes and prevented myelin loss following microglial envelopment. These findings directly implicate microglia in pathological myelin loss and support BTK inhibition as a therapeutic strategy to prevent demyelination by modulating microglia behavior.

neuroscience↗

bioRxiv2026

Entorhinal grid coding as a functional link between tau accumulation and episodic memory in human aging

Episodic memory decline is a common feature of cognitively normal aging, but its extent varies markedly across individuals. Although entorhinal tau pathology is thought to be a key contributor to episodic memory impairment, the neural mechanisms linking early tau accumulation to memory differences remain unclear. Grid-cell computations in the entorhinal cortex, which provide scaffolds for organizing experiences into episodic memories, offer one candidate mechanism. Here, we combined virtual-reality functional MRI, multivariate analysis, tau PET, and delayed word-list recall in cognitively normal older adults to test whether tau-related alterations in entorhinal coding are associated with worse episodic memory. Weaker left entorhinal grid-cell-like signal was associated with poorer memory performance, and individuals with higher left entorhinal tau burden showed weaker grid-cell-like signal. This association was specific to the canonical six-fold signal and was not explained by entorhinal volume, mean diffusivity, or intracortical myelination. A cross-sectional Bayesian mediation analysis further demonstrated that bilateral medial temporal tau burden is related to memory indirectly through left entorhinal grid-cell-like signal. Together, these findings provide evidence that entorhinal grid codes may constitute a functional pathway linking tau accumulation to memory variability in normal aging.

neuroscience↗

bioRxiv2026

A patient-centric therapeutic paradigm uncouples prostate cancer suppression from systemic metabolic collapse

The clinical benefits of cancer therapies are often compromised by the tolerable adverse effects that impair systemic organismal health and may evolve into latent life threats. Here, we identified profound abiraterone-induced but androgen-independent metabolic perturbations in prostate cancer patients and developed Lifehug-9892 to balance tumor therapy with systemic metabolic homeostasis. By integrating population cohorts with high-resolution metabolomics, we demonstrate that abiraterone induces profound systemic lipidomic dysregulation, characterized by the massive, pathological accumulation of desmosterol. Abiraterone inhibits but stabilizes DHCR24, leading to a metabolic trap in patients showing elevated levels of both desmosterol and cholesterol. Desmosterol accumulation is highly lipotoxic, potently triggering endothelial cell senescence and necrosis, macrophage foam cell formation, murine atherosclerosis, and hepatic senescence. To mechanistically uncouple and therapeutically rescue this systemic metabolic collapse, Lifehug-9892 was rationally designed to selectively retain on-target CYP17A1 inhibition while completely sparing DHCR24 function. Lifehug-9892 maintains potent tumor-suppressive activity while fully preserving the desmosterol-cholesterol metabolic axis and preventing systemic cardiovascular and hepatic damage. Our study uncovers a critical mechanistic link between drug-induced metabolic dysregulation and organismal health in cancer patients, providing a biochemical framework for developing patient-centric targeted therapies that preserve host homeostasis.

cancer biology↗

bioRxiv2026

Elevated hydrostatic pressure modulates endothelial junctional mechanotransduction through VE-cadherin remodelling and altered association with YAP1, EPS8: an endothelium-on-chip study

Endothelial dysfunction is a hallmark of numerous vascular pathologies and is strongly influenced by mechanobiological forces within the vascular microenvironment. While the effects of shear stress have been extensively investigated, the mechanisms by which elevated hydrostatic pressure regulates endothelial junctional organisation remain sparsely investigated. Here, we employed a microfluidic platform to investigate the combined effects of low shear stress (1.4 dyne/cm2) and elevated hydrostatic pressure (~3972 Pa) on endothelial junctional dynamics. Elevated hydrostatic pressure induced marked remodelling of VE-cadherin junctions, characterised by formation of serrated, finger-like structures accompanied by increased YAP1 nuclear localisation and reduced YAP1-VE-cadherin cytoplasmic colocalisation compared to shear stress alone conditions. Further, elevated hydrostatic pressure also demonstrated an increase in cytoplasmic accumulation of EPS8, an actin adaptor protein, and increased cytoplasmic EPS8-VE-cadherin colocalisation. These observations were accompanied by functional changes marked by increased endothelial permeability, and enhanced THP-1 monocyte adhesion, thus suggesting activation of mechanosensitive pathways linked to dynamic junctional reorganisation. Inhibition of PI3K at elevated hydrostatic pressure exhibited a thin VE-cadherin patterning and increased cytoplasmic EPS8-VE-cadherin colocalisation, thus demonstrating a prominent role for PI3K signalling in regulating the junction organisation. Interestingly, Piezo-1 activation using Yoda1 produced context-dependent effects. Under shear stress alone, Yoda1 promoted YAP1 nuclear translocation, reduced YAP1-VE-cadherin colocalisation, increased endothelial permeability but strikingly did not impact THP-1 adhesion compared to shear stress alone conditions. In contrast, under elevated hydrostatic pressure conditions, Yoda1 significantly reduced both endothelial permeability and THP-1 adhesion while increasing YAP1-VE-cadherin colocalisation and decreasing YAP1 nuclear accumulation. Collectively, these findings identify a previously underappreciated elevated hydrostatic pressure-Piezo-1-PI3K signalling axis that regulates endothelial barrier integrity and pro-adhesive endothelial activation through coordinated regulation of VE-cadherin, YAP1, and EPS8. These results highlight elevated hydrostatic pressure as a unique mechanobiological stimulus, distinct from that of shear stress alone and provide novel insights into mechanisms underlying microvascular dysfunction.

bioengineering↗

bioRxiv2026

Differential expression of NEAT1 in the corneal endothelium increases susceptibility to oxidative stress in Fuchs Endothelial Corneal Dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a disease of the corneal endothelium (CE) characterized by the loss of corneal endothelial cells (CECs) and guttae formation, ultimately resulting in corneal edema and vision loss. FECD primarily affects the central CE while sparing the peripheral CE, however the underlying mechanism contributing to the spatial differences remain unknown. Oxidative stress has been increasingly recognized as a key contributor to the pathogenesis of FECD, with CECs being particularly susceptible to damage from reactive oxygen species (ROS), high metabolic activity and ultraviolet induced DNA damage. The non-proliferative nature of CECs, along with the accumulation of oxidative damage can ultimately lead to CEC loss, a key feature of FECD. In this study, we induced oxidative stress with hydrogen peroxide (H2O2) on ex-vivo corneal specimens and observe increased cell death in the central region compared to the peripheral CE. To investigate these underlying differences, we performed bulk RNA sequencing (RNA-seq) on the central and peripheral regions of CE from FECD and normal cadaveric donors. Pathway analysis identified an enrichment of genes involved in collagen and extracellular matrix between the central and peripheral regions of CE in both normal and FECD, as well as between normal and FECD CE. Intriguingly, we identified the long non-coding RNA (lncRNA), NEAT1 as a top differentially expressed gene, with reduced expression in the central CE compared to the peripheral CE and lower expression in FECD compared with normal CE. Using corneal endothelial cell lines and ex-vivo specimens from FECD patients and normal cadavers, we found decreased NEAT1 expression levels in FECD and increased susceptibility to H2O2-induced oxidative stress. We observed that NEAT1 knockdown in normal and FECD cells exacerbated H2O2-mediated oxidative stress, and that NEAT1 overexpression protected FECD cells. We report in this study, a novel insight in the spatial differences in gene expression in the CE and identify reduced expression of NEAT1 in the central CE as a potential contributor to oxidative stress-related cell death in FECD. These findings provide novel insight into FECD pathogenesis and why FECD pathology preferentially affects the central CE. Antioxidants targeting NEAT1 signaling could be developed into novel therapeutics aimed at preventing FECD pathogenesis.

cell biology↗