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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2026

NFIC-mediated CaSR endocytosis defines a hyperactive TOMM20highCHGAhigh oxyphil cell state as a pathological driver of autonomous secondary hyperparathyroidism

Secondary hyperparathyroidism (SHPT) is a debilitating complication of chronic kidney disease. Its clinical management is frequently compromised by calcimimetic resistance, a refractory state primarily driven by the progressive downregulation of the membrane calcium-sensing receptor (CaSR). Despite the centrality of CaSR as a therapeutic target, the mechanisms governing its aberrant expression and membrane localization remain incompletely elucidated. Here, we generated a single-cell transcriptomic atlas of human parathyroid tissues from SHPT and primary hyperparathyroidism (PHPT) patients, uncovering a unique stromal-immune niche that is specifically induced by uremic stress in SHPT. Our data also observed a striking dissociation between CaSR mRNA and its abundance as a membrane protein in SHPT tissues. Pseudotime trajectory analysis showed a progressive decline in CaSR pathway activity and a concomitant increase in endo-lysosomal activity along the trajectory, terminating in pathological oxyphil cells as the endpoint of chief cell differentiation in SHPT. Mechanistically, Nuclear Factor I C (NFIC) transcriptionally activated clathrin light chain B (CLTB) and Ras-related protein Rab7a (RAB7A) to trigger clathrin-mediated endocytosis and lysosomal degradation of CaSR, thus reducing its membrane abundance. This degradative program was further validated by multiplex immunofluorescence in TOMM20highCHGAhigh pathological oxyphil cells in human SHPT tissues. To translate these mechanistic findings into a clinically actionable strategy, we repurposed the clinically approved lysosomal inhibitor hydroxychloroquine (HCQ) to block this CaSR degradation pathway. In patient-derived xenograft (PDX) mouse models, co-administration of HCQ and cinacalcet acted synergistically to restore membrane CaSR expression, normalize serum PTH and calcium levels and suppress parathyroid tumor growth more effectively than monotherapies. Collectively, our single-cell-guided study identifies an NFIC-driven endo-lysosomal program as a previously unrecognized mechanism underlying CaSR downregulation and calcimimetic resistance in SHPT, and establishes HCQ repurposing as a clinically tractable therapeutic strategy for patients with refractory SHPT.

cell biology↗

bioRxiv2026

An integrated human forebrain organoid reveals microglia-mediated CD8⁺ T cell recruitment and neuroimmune dysfunction in Alzheimer's disease pathology

Genetic evidence implicates immune dysfunction in Alzheimers disease (AD), yet the neuroimmune mechanisms operating in human tissue remain poorly defined. Here, we establish a modular human forebrain organoid platform that systematically integrates iPSC-derived microglia and CD8+ T cells to reconstitute multicellular Alzheimers disease pathology. This system enables functional interrogation of both innate and adaptive immune components in a human-relevant context. Using this platform, we demonstrate that microglia mediate amyloid-{beta} clearance and neuronal maturation but also drive inflammatory activation and recruit CD8+ T cells through CCL4/5 signaling via CCR1/5 and CXCR3, establishing a neuroinflammatory feedback loop. Pharmacological targeting of CCR5 or CXCR3 blocks T cell recruitment and modulates autophagy in a microglia-dependent manner. This modular organoid platform provides a versatile tool for dissecting neuron-immune interactions and enables cell-type-specific therapeutic screening in human neuroinflammatory disease models. Highlights1) A modular human forebrain organoid platform integrating innate (microglia) and adaptive (CD8+ T cells) immunity recapitulates key features of the human neuroimmune environment 2) Enables mechanistic dissection of multicellular interactions underlying Alzheimers disease pathology 3) Overcomes limitations of traditional animal models by resolving human-specific, cell-type-specific neuroimmune mechanisms 4) Establishes a new approach methodology for studying neuroimmune disorders and advancing drug discovery

bioengineering↗

bioRxiv2026

A human GBA-L444P transgene drives early and persistent dopamine neurotransmission deficits and alpha-synuclein pathology in a mouse model of early Parkinson's disease

BackgroundHeterozygous mutations in the GBA1 gene encoding the enzyme glucocerebrosidase (GCase) represent the most common genetic risk factor for developing Parkinsons disease (PD). The underlying mechanisms by which GBA1 mutations lead to PD through both loss- and gain-of-function effects remain unclear. There is a strong rationale for the generation and characterisation of a humanised GBA1 mouse model to allow the effect of GBA1 mutations on GCase function to be studied within the context of the human protein. MethodsWe have generated novel humanised mutant GBA-L444P and wild type GBA-WT mouse models using BAC recombineering and site-specific integration allowing the incorporation of the whole GBA1 locus as a transgene, including the endogenous promoter, all exons and introns, and flanking regions. Our experimental design crossed each GBA1 transgene onto a Gba+/- background and included Gba+/- littermate controls in our cohorts, allowing us to explore both the loss- and gain-of-function of GBA1 mutations. We have carried out "deep phenotyping" to characterise these mice by biochemical, stereological and behavioural testing, and assess dopamine release and content using fast-scan cyclic voltammetry and high performance liquid chromatography. ResultsThe GBA-L444P mice showed a significant reduction in GCase activity by 18 months of age and preferentially expressed a high molecular weight form of the GCase protein, likely due to retention in the ER and aberrant glycosylation. The GBA-L444P, but not Gba+/-, mice demonstrated an early and persistent reduction in dorsal striatal dopamine release in the absence of any dopaminergic cell loss or deficits in dopamine synthesis or reuptake, compared to human wild-type controls. GBA-L444P and Gba+/- mice developed an accumulation of oligomeric -synuclein pathology, but only GBA-L444P mice demonstrated subtle but significant changes in behaviour. ConclusionsThe novel humanised GBA-L444P mouse model described here helps to resolve gain- or loss-of-function effects of GBA1 mutations seen in Parkinsons as well as providing a novel set of models to investigate the human protein. Our work demonstrates that changes in dopamine release and behavioural deficits arise from a gain-of-function mechanism, whereas -synuclein pathology arises from GCase loss-of-function.

neuroscience↗

bioRxiv2026

Integrated Transcriptomic and Functional Analysis Reveals Tissue-Specific Molecular Pathology in Adolescent Idiopathic Scoliosis

Adolescent idiopathic scoliosis (AIS), the spontaneous development of a lateral spine curvature during puberty, is the most common pediatric spine disorder, affecting [~]3% of children worldwide. As the underlying etiology remains unclear, AIS is treated purely symptomatically, initially by bracing and ultimately by highly invasive, costly surgeries. Genome-wide association studies (GWAS) have identified numerous risk loci in non-coding genomic regions, making it difficult to link them to a biological function. To address this, we performed a multi-tissue investigation to connect genetic risk to tissue-specific molecular pathology. We conducted RNA sequencing on the primary tissues implicated in AIS, paraspinal muscle and spinal cartilage, from patients and unaffected controls. In paraspinal muscle, we identified differentially expressed genes (DEGs) enriched for pathways related to muscle structure, myogenesis, and metabolism. Key upregulated genes include the transcription factor EGR1 and structural components such as MYH1. In spinal cartilage, we found enrichment of genes related to TGF{beta} and FoxO signaling, as well as metabolic pathways. Notably, genes crucial for chondrocyte differentiation (e.g. SOX5 and SOX6) were significantly downregulated. We then examined genes at known GWAS loci and found that several risk-associated genes were differentially expressed in one or both tissues. To investigate the function of non-coding variants at these loci, we identified and validated several enhancer elements harboring AIS risk SNPs at the BCL2, ADGRG6, BNC2, and FTO loci. We reveal distinct pathological signatures in muscle and cartilage and lay the foundation for connecting non-coding genetic risk to the dysregulation of key developmental and structural pathways.

genetics↗

bioRxiv2026

Hypothalamic MCH neurons links tau pathology to sleep disruption

Sleep disruption is an early and pervasive feature of Alzheimers disease (AD), yet the circuit mechanisms linking tau pathology to sleep-wake dysfunction remain unresolved. Here, we identify melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH) as a critical node disrupted in tauopathy. Longitudinal EEG/EMG recordings in PS19 mice reveal progressive impairments in sleep architecture and homeostasis. Histological analyses revealed significant degeneration of both MCH neurons and the neighboring hypocretin (Hcrt) neuronal population in the LH at late stages of tauopathy. In vivo fiber photometry recordings demonstrated a selective functional impairment of MCH neurons, characterized by reduced activity during REM sleep, whereas Hcrt neuronal activity remained largely preserved. In addition, cell-autonomous expression of mutant tau in MCH neurons recapitulates sleep disruption, establishing a causal role. Despite tauopathy-induced neuronal loss and reduced endogenous activity, optogenetic and chemogenetic activation show that MCH neurons retain functional capacity, and their activation restores sleep in aged PS19 mice. Together, these findings define a circuit mechanism linking tau pathology to sleep and identify MCH neurons as a tractable therapeutic target.

neuroscience↗

bioRxiv2026

Kinematics to Kinetics: Evaluating OpenGRF for Scalable Ground Reaction Force Estimation in Healthy and Pathological Gait

Ground reaction forces (GRFs) are important markers of gait impairment and rehabilitation, but direct measurement with force plates is expensive and limited to laboratory settings. OpenGRF is an open-source framework that estimates GRFs from motion-capture data using musculoskeletal modeling, yet its validity in pathological gait remains uncertain. This study evaluated the accuracy of OpenGRF for estimating three-dimensional GRFs during gait in healthy adults and in people with Parkinsons disease (PD), stroke, hip osteoarthritis (HOA), and total hip arthroplasty, and assessed its ability to reproduce clinically relevant GRF peak magnitudes and timings. OpenGRF estimates were compared with force-plate measurements in healthy participants and in cohorts with PD (OFF/ON medication), stroke, and HOA before surgery (M0) and 6 months after surgery (M6). Accuracy was quantified using root mean square error (RMSE), normalized RMSE (NRMSE), and Pearson correlation coefficients (PCC). Peak analyses examined biases in anterior-posterior (AP) braking and propulsive peaks, first and second vertical peaks (V1, V2), and the main mediolateral peak, as well as timing shifts across the gait cycle. One-dimensional statistical parametric mapping tested waveform differences (p = 0.01). OpenGRF reproduced overall GRF profiles across groups. Vertical GRF showed the best agreement (PCC 0.84-0.94; NRMSE 0.14-0.23), whereas mediolateral GRF showed low absolute error (RMSE 1.45-1.95 %BW) and moderate-to-good agreement (PCC 0.70-0.82). AP GRF was least accurate (PCC 0.61-0.73), especially during propulsion in PD (NRMSE up to 0.39). OpenGRF can reasonably estimate GRFs in healthy and pathological gait and may support kinetic gait assessment when force plates are unavailable.

bioengineering↗

bioRxiv2026

Intra-slide calibration technology improves immunohistochemical harmonization within and between anatomic pathology laboratories

The reproducibility of immunohistochemistry in tumor tissue analysis across reference labs remains a persistent challenge. We tested the extent to which an intra-slide calibration technology mitigated discprepencies in inter-laboratory assays of p53 immunohistochemical (IHC) reactions in brain biopsies of glioblastoma (GB), IDH-wildtype. Intra-slide calibration technologies apply a 0-100% concentration scale incorporating primary surrogate and secondary antibodies to generate a standardized curve for DAB precipitation. IHC from GB samples was performed independently by pathology departments from two different hospital laboratories and were digitalized at 40x magnification using Aperio Image Scope software. Feature extraction, including intensity and texture parameters was performed using the EBImage package in R, followed by UMAP dimensionality reduction and DBSCAN clustering analysis. Our results show significant differences in intensity and texture clustering patterns between laboratory tissue samples and intra-slide calibration technology ruler caused by the different laboratories. Intra-slide calibration technology coupled with polynomial regression analysis improved ~90% the data harmonization. Our findings demonstrate a key role for computational pathology using intra-slide calibration technology to enable intra-laboratory consistency and inter-laboratory reproducibility. These advances strengthen the reproducibility of diagnostic assessments and support more objective, data-driven decision-making in neuro-oncology.

bioinformatics↗

bioRxiv2026

A Unified Spatial AI Framework for Cross-Domain Tissue-State Analysis in Trauma, Oral, and Cardiovascular Pathology

ObjectiveTo develop a cross-domain spatial AI framework for identifying conserved tissue-state organisation across trauma, oral disease, and cardiovascular tissue using spatial transcriptomic data. MethodsFour public spatial transcriptomic datasets spanning wound healing, periodontitis, oral squamous cell carcinoma, and cardiac tissue were integrated using recurrence modelling, graph-based spatial learning, fuzzy tissue-state analysis, and tensor decomposition. Cross-domain coupling, spatial fragmentation, recurrence structure, and permutation-based topological validation were evaluated. ResultsSix conserved fuzzy tissue states were identified, dominated by extracellular matrix remodelling, fibroblast/stromal activation, endothelial signalling, and inflam-matory pathways. Latent embedding analysis demonstrated strong overlap between trauma and oral domains, while cardiovascular tissue exhibited more compact spatial organisation. Oral inflammatory tissue showed the highest fragmentation, whereas cardiovascular tissue demonstrated greater recurrence coherence. Tensor decomposition identified conserved stromal-remodelling programmes across domains. Permutation testing confirmed significantly elevated graph modularity and reduced spatial entropy relative to null distributions. ConclusionThe proposed framework identified conserved spatial tissue-state architecture linking wound healing, oral pathology, and cardiovascular tissue despite differences in tissue origin, pathology, and acquisition technology. SignificanceThese findings demonstrate the potential of spatial AI for investigating conserved stromal and inflammatory microenvironmental organisation across clinically related disease systems and may support spatial biology research in trauma-oral-systemic health.

bioinformatics↗

bioRxiv2026

ESCRT Machinery Dysfunction in Motor Neurone Disease: TSG101, CHMP2B, and VPS4a Differentially Regulate TDP-43 Pathology, Autophagy, and Exosome Biogenesis

Motor Neurone Disease (MND) is characterised by progressive degeneration of upper and lower motor neurons, accompanied by cytoplasmic mislocalisation and hyperphosphorylation of TDP-43 -- hallmarks that implicate failure of endolysosomal proteostasis. The Endosomal Sorting Complexes Required for Transport (ESCRT) pathway governs multivesicular body (MVB) formation, lysosomal cargo delivery, and autophagosome closure, yet its expression profile in human MND tissue and mechanistic contribution to disease pathology have not been established. Here, we report subunit-specific dysregulation of ESCRT proteins in postmortem motor cortex and spinal cord from MND patients: CHMP2B (ESCRT-III) is significantly upregulated in both regions, whilst TSG101 (ESCRT-I) and VPS37A (ESCRT-I) are significantly downregulated in motor cortex, indicating a region-specific remodelling of the ESCRT network. In a tunicamycin-induced ER stress model using NSC-34 motor neuron-like cells and primary cortical neurons, TSG101 overexpression reduced total and phosphorylated TDP-43, suppressed mTOR signalling, and restored autophagic flux, whereas TSG101 knockdown exacerbated TDP-43 accumulation and cytoplasmic mislocalisation. CHMP2B modulation selectively regulated TDP-43 phosphorylation without altering total TDP-43 levels, consistent with a casein kinase 1-dependent mechanism operating independently of bulk autophagy. Both TSG101 and VPS4a were required to maintain neuronal CD9 tetraspanin localisation to early endosomes; their depletion redirected CD9 to late endosomal and lysosomal compartments under ER stress. Extracellular vesicle characterisation revealed a functional divergence: TSG101 is required for general exosome biogenesis, whereas VPS4a ATPase activity specifically mediates loading of pathological TDP-43 cargo into EVs. Dynamic light scattering confirmed that ER stress and ESCRT modulation produce distinct, condition-specific alterations in EV size and polydispersity. These findings establish ESCRT dysfunction as a multifaceted contributor to MND pathogenesis and identify TSG101, CHMP2B, and VPS4a as mechanistically distinct therapeutic targets warranting preclinical validation.

neuroscience↗

bioRxiv2026

HnRNPAB-targeted antisense oligonucleotides ameliorate tau pathology and cognitive deficits by modulating Alzheimers disease-associated alternative splicing

Aberrant alternative splicing alters multiple disease-associated splicing events, including MAPT exon 10 inclusion linked to tau pathology, and thereby impacts Alzheimers disease (AD) progression. Heterogeneous nuclear ribonucleoprotein AB (hnRNPAB) functions as a splicing regulator, yet its roles in AD remain poorly defined. Here, we identified AB332, the full-length isoform of hnRNPAB, as a novel repressor of MAPT exon 10 inclusion. AB332 binds a conserved AAUAU motif and recruits RBMX and RBMXL1 through its RRM and glycine-rich domains to assemble a complex. Beyond MAPT, AB332 modulates a network of splicing events in multiple AD-associated genes, including STAG2, ApoER2, MCL-1, PICALM, and zDHHC7. Importantly, the exon 7-skipping isoform AB285 lacks these activities. Transcriptomic analysis of post-mortem brain tissues from AD patients revealed reduced expression of hnRNPAB, while selective downregulation of AB332 was confirmed in the hippocampus of 3xTg AD mice. We performed a systematic antisense oligonucleotide-tiling screen targeting hnRNPAB exon 7 and its flanking intronic regions, identifying ASO30 that specifically upregulated AB332 expression. In 3xTg AD mice, ASO30 restored hippocampal AB332 levels, reduced pathological tau phosphorylation, and rescued cognitive deficits. These findings define a molecular mechanism by which AB332 regulates AD-associated splicing events, thereby providing a therapeutic strategy targeting hnRNPAB for AD. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/736008v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@621096org.highwire.dtl.DTLVardef@2f01b1org.highwire.dtl.DTLVardef@182e6forg.highwire.dtl.DTLVardef@190afd3_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2026

TRIM9 Determines Sex-Specific β-Amyloid/Cellular Prion Protein/mGluR5 Complex Formation and Pathological Signaling in Alzheimer's Disease Mice

Biological sex is a major determinant of Alzheimers disease prevalence, yet the molecular mechanisms underlying sex-specific vulnerability remain largely unknown. Metabotropic glutamate receptor 5 (mGluR5) functions as a co-receptor for {beta}-amyloid (A{beta}42) oligomer/cellular prion protein (PrPC)-mediated pathogenic signaling in males but not females, establishing a sex-dimorphic node in {beta}-amyloid pathophysiology whose regulatory basis is undefined. Using quantitative proteomic analysis, we identify the E3 ubiquitin ligase TRIM9 as a novel mGluR5-interacting protein and a previously unrecognized sex-specific regulator of the A{beta}42/PrPC/mGluR5 complex. TRIM9 selectively associates with mGluR5 in male but not female APP/PS1 mouse brain and is required for mGluR5 to serve as a co-receptor for PrPC-dependent A{beta}42 oligomer binding. Genetic deletion of TRIM9 abolishes A{beta}42/PrPC/mGluR5 complex assembly in male APP/PS1 mice demonstrating that TRIM9 is an essential scaffold for male-specific A{beta}42 signal transduction. Loss of TRIM9 in males further reduces {beta}-amyloid pathology by restoring Akt/GSK3{beta}/ZBTB16-dependent autophagic flux, linking disruption of this complex to a defined downstream proteostatic mechanism. Together, these findings establish TRIM9 as a critical molecular determinant coupling male-specific A{beta}42/PrPC/mGluR5 complex assembly to downstream neurodegenerative signaling and {beta}-amyloid pathology. They reveal an unappreciated layer of sex-dependent complexity in mGluR5 pharmacology and identify disruption of the TRIM9/mGluR5 interaction as a potential male-specific therapeutic strategy for Alzheimers disease. Significance StatementThe molecular basis of sex differences in Alzheimers disease vulnerability remains unresolved. We show that mGluR5 functions as a male-specific co-receptor for pathogenic A{beta}42/PrPC signaling and identify the E3 ubiquitin ligase TRIM9 as the factor governing this dimorphism. TRIM9 selectively assembles the A{beta}42/PrPC/mGluR5 complex in male brain, and its genetic deletion disrupts complex formation while restoring Akt/GSK3{beta}-dependent autophagic clearance of amyloid. These findings define a sex-specific signaling axis underlying {beta}-amyloid pathogenesis and establish TRIM9 as a candidate target for sex-informed Alzheimers therapeutics.

neuroscience↗

bioRxiv2026

Clusterin regulates microglial inflammation and cognitive function independent of amyloid pathology in Alzheimer's disease

Clusterin (CLU) is a major genetic risk factor for late-onset Alzheimers disease (AD), yet the mechanism underlying this risk remains unclear. This study investigated the role of CLU in regulating microglial inflammation, amyloid pathology, and cognitive function in CLU-deficient and AD models. CLU synthesis and secretion in microglia were highly dynamic, with minimal expression at rest but markedly increased expression upon pro-inflammatory stimulation. CLU deficiency amplified microglial activation and inflammatory responses, whereas introducing recombinant CLU protein reduced microglial inflammation. In a human mutant APP knock-in AD mouse model, loss of CLU impaired learning and memory despite a reduced amyloid burden. snRNA-seq analysis further revealed that CLU loss disrupted the balance between excitatory and inhibitory neurons. These findings provide novel insights indicating that CLU likely functions as a negative feedback regulator of microglial activation and inflammation, thereby promoting microglial resolution and neuronal homeostasis, and consequently, cognitive outcomes independent of amyloid pathology.

neuroscience↗

bioRxiv2026

Distinct extracellular matrix states uncouple collagen accumulation from pathological fibrosis in Duchenne muscular dystrophy

Fibrosis severity is routinely inferred from collagen abundance, although whether collagen quantity determines pathological fibrosis remains unclear. In Duchenne muscular dystrophy (DMD), chronic muscle injury and inflammation drive extracellular matrix accumulation, making these processes difficult to disentangle. We exploit sarcospan overexpression in mdx mice, a model of DMD (mdxTG), which improves membrane integrity and muscle function despite persistent matrix remodeling. mdxTG muscle accumulates more collagen than mdx yet lacks its dense macrophage-rich scars. Matrisome proteomics and spatial transcriptomics reveal compositionally and spatially distinct matrix states, while decellularized mdxTG matrix protects myotubes from membrane damage relative to mdx matrix. Despite these differences, both dystrophic matrices remain stiff and induce nuclear YAP in fibro-adipogenic progenitors. Verteporfin suppresses collagen production and reduces fibrosis in vivo, while nuclear YAP is increased in FAPs from patients with DMD. Thus, collagen abundance alone does not define pathological fibrosis; matrix organization, biological activity, and mechanosignaling distinguish functionally distinct fibrotic states.

physiology↗

bioRxiv2026

From Routine Pathology to Precision Oncology: Automated FFPE Tissue Processing for Large-Scale Molecular Studies

Melanoma incidence continues to rise globally, with formalin-fixed paraffin-embedded (FFPE) tissue archives representing an invaluable resource for large-scale retrospective proteomic studies. However, inconsistent deparaffinization remains a critical pre-analytical bottleneck limiting protein yield, reproducibility, and downstream data quality. In this study, we developed and validated a fully automated FFPE deparaffinization workflow using the Fluent(R) 780 liquid handling workstation (Tecan (C)) and evaluated its performance against a conventional manual protocol in a cohort of 54 patients with primary cutaneous melanoma, predominantly at early AJCC 8th edition stage I-II. The automated workflow achieved superior protein identification (6,146 {+/-} 860 vs. 4,941 {+/-} 1,091 proteins; p < 0.0001) with lower technical variability, while maintaining highly comparable global proteomic profiles as confirmed by principal component analysis and hierarchical clustering. A total of 8,305 proteins (96.1%) were identified by both methods, supporting the reproducibility and equivalence of the automated approach. Patients were stratified by the presence (N=21) or absence (N=33) of histological regression in the primary tumor. Proteomic comparison revealed 97 upregulated and 226 downregulated proteins in regressing melanomas, with pathway enrichment analysis demonstrating elevated mitochondrial and translational activity alongside reduced innate immune and complement pathway activation in the regression group. No statistically significant differences in overall, disease-free, or progression-free survival were observed between groups, consistent with the early-stage composition of the cohort. Digital pathology validated tissue morphology preservation across processing conditions. These findings support the integration of automated FFPE processing with proteomic and digital pathology workflows as a scalable platform for precision melanoma research. TOC Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/744404v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1a3ea5dorg.highwire.dtl.DTLVardef@6fb8edorg.highwire.dtl.DTLVardef@d60a4dorg.highwire.dtl.DTLVardef@3e47b6_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2026

CSF complement proteins are associated with early tau pathology and synaptic damage in an asymptomatic population at risk of Alzheimer's disease

Complement-mediated neuroinflammation has been implicated in Alzheimer's disease (AD), but its role during the pre-symptomatic phase of the disease remains unclear. In the PREVENT-AD cohort of cognitively unimpaired individuals at increased familial risk of AD, we investigated whether CSF complement proteins relate to early AD pathology and synaptic dysfunction, then assessed our results' reproducibility across the clinical AD spectrum. Baseline CSF C1q, C3, C3b, and Factor H were measured in relation to CSF AD biomarkers, synaptic proteins, cognition, MRI volumetry, and amyloid and tau PET. Key findings were then examined in 708 participants from ADNI spanning cognitively normal, mild cognitive impairment (MCI), and dementia stages of AD. In PREVENT-AD, C1q was positively associated with CSF P-tau181, T-tau, and multiple synaptic markers including ADAM23, GAP43, SNAP25, and SYT1. Factor H showed similarly strong positive associations with P-tau181, T-tau, ADAM22, ADAM23, GAP43, and SYT1. By contrast, C3 showed minimal associations, while C3b displayed weaker positive relationships with P-tau181, T-tau, ADAM22, and ADAM23. Complement proteins were not robustly associated with amyloid or tau PET, and only C1q related to lower global cognitive performance. In ADNI, C1q emerged as the most consistent analyte, showing positive associations with tau, neurofilament light, and synaptic markers across all diagnostic groups. C3 exhibited predominantly negative associations, whereas C3b and Factor H showed stage-dependent relationships, particularly with evident neurodegeneration and synaptic injury in symptomatic individuals. These findings identify complement dysregulation, especially involving C1q, as an early correlate of tau-linked synaptic pathology, and support a role for complement activation in the AD molecular cascade.

neuroscience↗

bioRxiv2026

Mitigation of Parkinson's Disease Pathology in C. elegans by Marine Bacterium Kocuria rhizophila via Ferroptosis Suppression

Parkinson's disease (PD) is a progressive neurodegenerative condition characterized by the loss of dopaminergic (DA) neurons and alpha-synuclein aggregation, with ferroptosis playing a critical pathological role. This study investigated the neuroprotective potential of Kocuria rhizophila strain CDMP12, a marine bacterium isolated from the Gulf of Mannar, India, using Caenorhabditis elegans models of PD. Dietary supplementation with K. rhizophila (CDMP12) significantly preserved DA neuron structure, rescued neuro-sensory and motor deficits, and attenuated both alpha-synuclein expression in the C. elegans models. Transcriptomic and qRT-PCR analyses revealed that CDMP12 systematically suppressed ferroptosis by significantly downregulating iron and lipid regulatory genes such as smf-3, ftn-1, and acs-4, while upregulating the protective antioxidant gene gpx-1. Furthermore, BODIPY staining demonstrated that CDMP12 treatment markedly reduced lipid peroxidation, lowering the oxidized-to-non-oxidized lipid ratio in PD worms. Collectively, these findings identify K. rhizophila (CDMP12) as a promising marine-derived neuroprotective candidate that mitigates PD-associated pathology, accompanied by reduced alpha-synuclein burden, preservation of DA neuronal function, and attenuation of ferroptosis-associated molecular and lipid peroxidation signatures.

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

Hierarchical temporal transformer for cancer grade prediction and cross cancer transfer learning from pathology reports

Language models for cancer clinical reports carry two blind spots. They read each report in isolation, ignoring how a patients disease changes across visits, and they are evaluated only on cancer types present in their training data. We present the Hierarchical Temporal Transformer (HTT), a two-level architecture that addresses both. Level 1 encodes each report with BiomedBERT adapted by low-rank adaptation (LoRA). Level 2 is a temporal transformer that reads a patients full report sequence using a continuous-time positional encoding built from the measured number of days between visits, with learnable cancer-type embeddings supplying per-family conditioning. Two experiments test the two capabilities separately, since no fully open corpus contains longitudinal reports for many cancer types. On a controlled synthetic corpus of sequential radiology reports, in which progression phrases are inserted from templated trajectories, HTT reaches a validation AUROC of 0.942 against 0.881 for a single-report baseline and transfers to held-out pancreatic cancer at 0.995 against 0.949 while the two models are indistinguishable on a 60-patient test set. On 4,786 real pathology reports from the TCGA-Reports corpus spanning 14 cancer types HTT predicts tumor grade for three types withheld entirely from training, reaching AUROC 1.000 on thyroid carcinoma, 0.960 on sarcoma and 0.808 on lung squamous cell carcinoma. The mean held-out AUROC of 0.923 equals the in-distribution test AUROC of 0.923, so transfer to unseen cancer families incurred no measurable penalty. Ablation on the real corpus shows that the transfer is carried by the pre-trained encoder rather than by the temporal components, which, with one report per patient, contribute 0.39 AUROC points. Grade-related pathological language therefore appears to be learnable in a cancer-type agnostic way, which points toward unified cancer NLP systems that require no per-type retraining.

bioinformatics↗