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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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At least 181 records · Page 10Linked to original sources

bioRxiv2019

Pathological Tau Induces Neurodegeneration by Sequestering and Inhibiting LSD1

Tauopathies are a class of neurodegenerative diseases associated with pathological tau. Despite many advances in our understanding of these diseases, the direct mechanism through which tau contributes to neurodegeneration remains poorly understood. Previously, our lab implicated the histone demethylase LSD1 in tau-induced neurodegeneration by showing that LSD1 localizes to pathological tau aggregates in Alzheimers disease cases, and that it is continuously required for the survival of hippocampal and cortical neurons in mice. Here, we utilize the P301S tauopathy mouse model to demonstrate that pathological tau can exclude LSD1 from the nucleus in neurons. In addition, we show that reducing LSD1 in these mice is sufficient to highly exacerbate tau-mediated neurodegeneration and tau-induced gene expression changes. Finally, we find that overexpressing LSD1 in the hippocampus of tauopathy mice, even after pathology has formed, is sufficient to significantly delay neurodegeneration and counteract tau-induced expression changes. These results suggest that inhibiting LSD1 via sequestration contributes to tau-mediated neurodegeneration. Thus, LSD1 is a promising therapeutic target for tauopathies such as Alzheimers disease. SIGNIFICANCE STATEMENTWe have made the novel discovery that pathological tau functions through the histone demethylase LSD1 in the Alzheimers disease pathway. Thus, we have identified a mechanism that links tau to the downstream neuronal dysfunction pathways. This step can potentially be targeted therapeutically, after the onset of dementia symptoms, to block the progression of dementia in Alzheimers disease patients.

neuroscience↗

bioRxiv2025

Enhanced ex vivo 3D whole-brain mapping and automated analysis of Parkinson's disease pathologies in mice

The spatiotemporal relationships among -synuclein inclusion formation, dopaminergic degeneration, and white matter microstructural changes remain poorly defined. To address this, we unilaterally injected preformed fibrils (PFFs) or monomeric -synuclein into the substantia nigra pars compacta (SNc) of wild-type mice. At 12 and 20 weeks post-injection (wpi), we performed ex vivo magnetic resonance imaging (MRI) at 9.4T to assess microstructural, volumetric and paramagnetic changes, along with light-sheet microscopy (LSM) to map -synuclein aggregates, and dopaminergic neuron at single-cell resolution across the whole brain. We developed a Python-based, automated registration pipeline that achieves <40 {micro}m alignment error between ex vivo MRI and LSM and computes clearing-induced distortion, enabling scalable deformation analysis and multimodal multiscale data integration. Unilateral SNc injection of -syn PFFs induced dense phospho--syn pathology in the ipsilateral SNc at 12 wpi, which decreased by 20 wpi in parallel with the loss of tyrosine hydroxylase-positive dopaminergic neuron. Pathogenic -synuclein spreads along with dopaminergic denervation in the nigrostriatal pathway to the ipsilateral striatum and contralateral SNc. Our ex vivo MRI-LSM platform provides a scalable, open-source framework for understanding circuit-level and whole-brain propagation of pathology in an -synucleinopathy model and beyond. HighlightsO_LIOpen-source, automated pipeline aligns ex vivo 9.4T MRI with light-sheet microscopy (LSM) at <40 {micro}m error, quantifies clearing-induced tissue distortion, and enables multiscale, whole-brain multimodal analysis. C_LIO_LIWhole-brain, single-cell-resolution mapping of -synuclein pathology and dopaminergic neuron loss in an -synucleinopathy mouse model using an optimized iDISCO+ protocol that achieves uniform antibody penetration even in dense regions like the striatum. C_LIO_LIUnilateral SNc injection of -syn PFFs drives spread of p--syn pathology along the nigrostriatal pathway to the ipsilateral striatum, BST, CEA, and contralateral SNc, along with dopaminergic degeneration. C_LIO_LIIpsilateral SNc shows high pS129 pathology at 12 weeks post-injection but significant reduction by 20 wpi, concurrent with loss of tyrosine hydroxylase-positive neurons. C_LIO_LIMultiparametric MRI reveals microstructural and iron-related alterations in striatum, SNc, and VTA, with cross-modal correlations linking pS129 burden, TH loss, and magnetic susceptibility changes. C_LI

neuroscience↗

bioRxiv2025

Neuronal PARIS-STAT3 axis drives tau pathology and glial activation in Alzheimers disease

PARIS, a substrate of Parkin, accumulates in Parkinsons disease and promotes disease progression. Here, we demonstrate that PARIS also contributes to Alzheimers disease by elevating STAT3 transcriptional activity, thereby inducing tau pathology, hippocampal atrophy, and glial activation. Genetic depletion of Paris reduced tau phosphorylation and cognitive decline in tauopathy mice, whereas neuron-specific PARIS overexpression caused tau accumulation, gliosis, and memory impairment. In contrast, astrocyte-specific overexpression did not induce pathology, indicating that PARIS acts in neurons to drive tau phosphorylation and glial activation. The pathological features induced by neuronal PARIS overexpression were rescued by STAT3 inhibition, demonstrating that PARIS-STAT3 signaling underlies these effects. Moreover, Paris knockout did not alter pathology in the amyloid-driven mouse model, highlighting specificity for tau pathology. Together, these findings reveal PARIS as a neuronal regulator of STAT3 signaling that exacerbates tau-mediated neurodegeneration and identify the PARIS-STAT3 pathway as a potential therapeutic target in Alzheimers disease.

neuroscience↗

bioRxiv2025

The Hemodynamic Response Function Varies Across Anatomical Location and Pathology in the Epileptic Brain

The hemodynamic response function (HRF) links neuronal activity to functional magnetic resonance imaging (fMRI) signals. While most fMRI studies use a "canonical" HRF, increasing evidence from studies of healthy subjects suggests that the HRF depends on anatomical location and disease states. Here, we investigate how HRF variability relates to anatomical location and pathology in the epileptic brain, using a large simultaneous electroencephalogram and fMRI dataset. Applying HRF deconvolution and temporal decomposition, we built the first whole-brain HRF library specific to epilepsy, identifying four distinct shape groups. We mapped HRF features across parcellations of two atlases using novel Bayesian hierarchical models. In non-epileptogenic regions, HRF shape and spatial distributions align with findings from healthy subjects. Within pathological regions, they vary significantly according to pathology. Our results indicate that HRF variability is associated with pathology, in addition to its dependence on anatomical location, motivating region- and pathology-based HRF modulation in epilepsy studies.

neuroscience↗

bioRxiv2025

Flu Virus Infection in Juvenile Mice Leads to Lifelong Multi-Organ Damage and Parkinsonian Pathological Changes in Aging

The widespread prevalence of Long COVID underscores the potential for viral infections to exert prolonged effects on hosts long after initial recovery. Despite this recognition, the long-term and even lifelong consequences of viral infections remain poorly understood. In this study, we infected juvenile mice with influenza viruses and systematically examined the lifelong effects (from 4 to 450 days post-infection) of these infections. Pathological analysis revealed persistent lifelong damage in multiple organs, including chronic lung inflammation and fibrosis, along with significant cardiac and renal pathology. Viral infection led to substantial neuronal loss in key brain regions of mice (hippocampal CA1, CA3, and striatum) during middle and old age. Strikingly, we identified two hallmark pathological features of Parkinsons disease - dopaminergic neuron degeneration and Lewy body-like -synuclein inclusions - in middle and aged infected mice. Transcriptomic profiling demonstrated sustained upregulation of inflammation-related genes in both lung and blood tissues, correlating with observed pathological changes. Lung-derived secreted proteins, encoded by differentially expressed genes, may mediate cross-organ communication affecting cardiac, renal, and neurological function. Brain transcriptome analysis at three months post-infection revealed downregulation of neurodevelopmental genes, potentially contributing to subsequent neuronal loss and Parkinsonian pathology. These findings collectively suggest that pulmonary influenza infection can induce systemic multi-organ effects through both secretory pathways and chronic inflammatory responses. The study offers crucial insights for developing more effective strategies to prevent and manage infectious diseases and their long-term sequelae.

microbiology↗

bioRxiv2025

Injury-induced CTE-like pathology emerges in a human multicellular in vitro brain model and reveals mitochondrial and neurovascular regulation.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease linked to repetitive mild head impacts, but no human-based experimental system exists to study injury-induced CTE-like pathology. Here, we establish a long-lived, human multicellular in vitro brain platform in which controlled mechanical injury induces key cellular features of CTE-like pathology. Injured cultures developed persistent tau phosphorylation, axonal degeneration, chronic inflammation, and metabolic dysfunction without widespread neuronal loss, consistent with progressive pathology rather than acute toxicity. To assess physiological relevance, we integrated transcriptomic profiles from the model with postmortem human CTE brain datasets. This analysis revealed striking convergence at the level of disease-associated modules and pathways, with endothelial cells emerging as critical contributors to CTE-like transcriptional programs. Using this human-based system, we further identified delayed mitochondrial dysfunction as a prominent and sustained feature of injury-induced pathology. Together, these findings establish the first human in vitro platform for studying injury-induced CTE-like pathology and identify neurovascular and mitochondrial regulation as central components of chronic neurodegeneration following repetitive mild brain injury.

neuroscience↗

bioRxiv2026

A Versatile AAV-TH-SNCA Model to Study Early α-Synuclein Pathology and Intervention

Adeno-associated viral (AAV)-mediated overexpression of human wildtype -synuclein (-syn) in the substantia nigra (SN) is a widely used approach to model Parkinsons disease (PD) in rodents. However, variability in the ability of AAV-based systems to induce nigrostriatal pathology and motor deficits has limited reproducibility across studies, especially in mice. Here, we systematically optimized key vector features - AAV serotype, promoter, viral titer - to establish a highly efficient and reliable mouse model of PD. We compared the tropism and expression efficiency of mixed AAV2/1 and AAV2/rh10 serotypes combined with three promoters - CMV enhancer/chicken {beta}-actin (CBA), human Synapsin (hSYN), and rat Tyrosine Hydroxylase (TH) - to drive human -syn gene (SNCA) expression in nigral dopaminergic neurons. The AAV.TH.SNCA vector, delivered at an optimized titer, achieved selective and sustained -syn overexpression in nigral neurons, resulting in nigro-striatal neurochemical changes and progressive motor deficits preceding overt neuronal loss. Fine tuning -syn expression proved critical for detecting early disease processes: lower AAV.TH.SNCA titer induced early pathological signatures, including -syn hyperphosphorylation and neuroinflammation, whereas higher titers produced robust nigrostriatal degeneration not achieved with other promoter constructs. Notably, we demonstrate that motor and neurochemical impairments can occur prior to dopaminergic cell death, implicating microglial activation and -syn pathology as primary drivers of dysfunction. This observation is consistent with human genetic evidence showing that triplication of the wild-type SNCA gene alone can cause Parkinsonian pathology, highlighting that our model enables the use of a single experimental reagent to investigate the molecular, cellular, and behavioral consequences of controlled increases in -syn expression. This novel AAV.TH.SNCA model provides a powerful and versatile platform for investigating mechanisms of a -syn-mediated neurotoxicity and for evaluating disease modifying interventions targeting early, pre-degenerative stages of PD. HighlightsO_LITitrated -syn expression uncouples early dysfunction from dopaminergic neuron loss C_LIO_LIAAV2/rh10-TH-SNCA model captures prodromal and degenerative PD stages C_LIO_LIMotor deficits arise from -syn pathology and nigral molecular changes before neurodegeneration C_LI

neuroscience↗

bioRxiv2026

Distinct Auditory Thalamocortical Pathologies Underlie Emerging Neurophysiological Dysfunction in a Cln3 Mouse Model of Batten Disease

CLN3 disease, the most common form of the Neuronal Ceroid Lipofuscinoses (NCLs), causes progressive cognitive decline and language impairment in humans. A pathological hallmark is the accumulation of storage material within neuronal lysosomes resulting from mutations in the CLN3 gene. We previously identified parallel deficits in auditory duration mismatch negativity (MMN), an electroencephalography (EEG)-based marker of auditory change detection, in individuals with CLN3 disease and in Cln3-/- mice. MMN-dependent auditory change detection relies on sensory-memory comparison mechanisms. However, the anatomical and neurophysiological substrates underlying this response in CLN3 disease remain unclear. Here, we investigated central auditory dysfunction in Cln3-/- mice by integrating immunohistochemical mapping of lysosomal storage pathology, using the canonical marker Subunit C of Mitochondrial ATP Synthase (SCMAS), with EEG analysis of auditory evoked potentials (AEPs). Neuropathological analyses revealed age-dependent and sex-divergent SCMAS accumulation across the auditory thalamocortical circuit, including the excitatory auditory thalamus, the inhibitory thalamic reticular nucleus, and the primary auditory cortex. In parallel, Cln3-/- mice exhibited age- and sex-dependent alterations in AEPs relative to wild-type controls. Importantly, an integrated measure of auditory thalamocortical SCMAS accumulation accounted for a substantial portion of age- and sex-matched variation in AEP responses, with stronger associations for the early N1 component than the later MMN component. Together, these findings link age-dependent and sex-divergent auditory neurophysiological deficits to region-specific lysosomal storage pathology within the auditory thalamocortical circuit in the Cln3-/- mouse model. This integrated functional-anatomical framework provides insight into circuit vulnerability and supports the development of translational neurophysiological biomarkers for CLN3 disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/729359v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@8dc148org.highwire.dtl.DTLVardef@8c918borg.highwire.dtl.DTLVardef@a7483dorg.highwire.dtl.DTLVardef@77d171_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISCMAS accumulates across the auditory thalamocortical circuit in Cln3-/- mice C_LIO_LIAccumulation shows distinct age- and sex-dependent regional trajectories C_LIO_LICln3-/- mice exhibit progressive alterations in auditory evoked potentials C_LIO_LIThalamic pathology is strongly associated with the early auditory N1 response C_LIO_LIHistology-EEG integration links circuit pathology to auditory dysfunction C_LI

neuroscience↗

bioRxiv2026

Placental pathology, circadian biology, and pathogenesis of spontaneous preterm birth: a pilot study of human placental gene expression profiling using a targeted HTG transcriptome panel

BACKGROUNDSpontaneous preterm birth (sPTB) remains the foremost cause of neonatal morbidity and mortality worldwide. Although histologic chorioamnionitis (HCA) and placental vascular abnormalities are frequently observed in sPTB, the molecular cascades linking these lesions to labor initiation remain poorly understood. Emerging evidence implicates circadian dysregulation and trophoblast dysfunction as additional drivers of sPTB. OBJECTIVEThis study aims to map placental pathology to distinct transcriptomic functional signatures that may precipitate sPTB, delineate the contribution of circadian regulation - both core-clock genes and circadian transcription-factor target sets (TFTs) - to sPTB, and identify placental cell-type-enriched and developmental pathway signatures that differ between sPTB and term deliveries. STUDY DESIGNWe performed bulk RNA sequencing on 32 formalin fixed, paraffin embedded placental specimens from 12 selected women (9 sPTB and 3 Term) in the POUCH Study cohort. Samples were selected for white ethnicity, maternal age 23-33years, and parity 1-4 to reduce heterogeneity within groups. An extraction-free HTG transcriptome panel assayed 19,398 protein-coding genes. Log2-fold changes of all genes were computed with limma adjusted for maternal age, gestational age, parity, placental region, placental pathology, and POUCHID (a clustering variable) for sPTB vs. Term and HCA/vascular lesion vs. no pathology (no placental pathology adjustment). Gene-set enrichment used 50 Hallmark sets (MSigDB) plus curated placental circadian, circadian TFT, cell-type, and developmental pathways or gene sets. RESULTSsPTB placentas displayed a global suppression of metabolic, secretory, and immune pathways (e.g., protein secretion, oxidative phosphorylation, Interferon responses, Complement, ROS, MYC Targets, TGF {beta}, mTORC1, and Coagulation) while KRAS Signaling Down and EMT were up-regulated. HCA-enriched sets (TNF/NF-{kappa}B, ROS, KRAS Up, IL-2/STAT5, Hypoxia, Interferon-{gamma}) were up-regulated, with EMT and Notch remaining down. Vascular abnormalities alone showed up-regulation of 12 Hallmark sets - including TGF-{beta}, TNF/NF-{kappa}B, ROS, pancreatic {beta}-cell stress, Hypoxia, Oxidative Phosphorylation, EMT, and mTORC1 - while Notch was down-regulated. When HCA co-exists with vascular abnormalities, the Hallmark profile becomes more inflammatory highlighting a synergistic exacerbation of innate immunity, oxidative stress, and programmed cell death with the 12 up-regulated sets (Complement, Interferon /{gamma}, TNF, ROS, Apoptosis, and Heme Metabolism). The exclusive downregulation of DNA Repair suggests compromised genomic integrity. Circadian gene-sets analysis revealed an up-regulated Regulation of Circadian Sleep Wake Cycle in sPTB but down-regulation of core clock pathway and suppressed circadian TF targets. Cell-type enrichment reveals increased trophoblast giant cells and IGFBP1-DKK1 positive fetal cells, with marked suppression of extravillous trophoblasts, syncytiotrophoblasts, villous cytotrophoblasts, and fetal myeloid cells. Placental developmental pathways were downregulated, indicating arrested trophoblast maturation. CONCLUSIONOur pilot analysis demonstrates sPTB placentas exhibit a global suppression of metabolic, secretory, and immune-modulatory programs and maladaptive trophoblast remodeling, whereas HCA and vascular abnormalities drove distinct inflammatory or hypoxic signatures. The shared and opposing Hallmark pathways across phenotypes highlight distinct yet overlapping pathogenic mechanisms. Dysregulated circadian pathways, consistent downregulated transcription factor target gene sets, and trophoblast-specific signatures implicate circadian misalignment and impaired placental maturation as key contributors to preterm parturition. These findings provide a mechanistic atlas linking placental pathology to sPTB and highlight potential targets for chronotherapeutic and cell-type-specific interventions. AJOG at a GlanceO_ST_ABSWhy was this study conducted?C_ST_ABSSpontaneous preterm birth remains a leading cause of neonatal morbidity. Histopathologic lesions of the placenta, particularly chorioamnionitis and vascular abnormalities, are common in preterm deliveries, yet the underlying molecular pathways are poorly understood. We sought to integrate functioning pathway profiles of placental histology, circadian biology, and cell types to identify mechanistic drivers of sPTB. Key findingsO_LIsPTB placentas showed widespread down-regulation of oxidative phosphorylation, mTORC1, hypoxia, interferon, and TNF/NF-{kappa}B pathways. C_LIO_LIHCA placentas up-regulated the same pathways (except androgen response), revealing a reciprocal inflammatory-hypoxic signature. C_LIO_LIVascular abnormalities displayed a distinct mix of up- and down-regulated pathways, suggesting divergent reparative responses. C_LIO_LIPlacentas with co-existing HCA and vascular abnormalities enriched more inflammatory Hallmark pathways: the 12 up-regulated sets (Complement, Interferon /{gamma}, TNF, ROS, Apoptosis, and Heme Metabolism) highlight a synergistic exacerbation of innate immunity, oxidative stress, and programmed cell death and the exclusive down-regulation of DNA Repair suggests compromised genomic integrity, which can contribute to premature placental senescence and preterm labor. C_LIO_LICircadian clock and multiple transcription-factor targets were enriched in sPTB, and trophoblast-specific signatures (giant, extravillous, syncytiotrophoblast) were prominent. C_LI What does this add to what is known?The study demonstrates a clear dichotomy between inflammatory and hypoxic molecular programs in sPTB and HCA, identifies circadian dysregulation as a potential contributor, and highlights trophoblast subpopulations as key players. These insights open avenues for targeted biomarkers and chronotherapy in preterm birth prevention.

bioinformatics↗

bioRxiv2026

Transglutaminase 2 Deletion Enhances Astrocyte-to-Neuron Metabolic Support and Attenuates Subacute Pathology Following Repetitive Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) is the most common form of central nervous system (CNS) injury and is often characterized by persistent neuroinflammation, metabolic dysregulation, and oxidative stress. Repetitive injuries compound these pathologies and lead to multifocal axonal injuries and long-term functional deficits. Despite the prevalence of mTBIs, the cellular mechanisms that facilitate or prevent recovery following injury remain poorly defined. Here, we extend our previous work on the role of the protein transglutaminase 2 (TG2) in CNS injury and we hypothesize that transcriptional regulation by TG2 restricts metabolic versatility in astrocytes following TBI, thereby impairing neuronal energetic support and worsening pathological outcomes. We utilized an established weight-drop model of repetitive mTBI followed by multi-parametric analysis of TBI pathology in complete TG2 knockout (TG2-/-) and wild type mice. At 28 days post-injury, TG2-/- mice showed marked attenuation of TBI pathology, compared to wild type mice, in vulnerable white matter and default mode network (DMN) regions, as assessed by diffusion magnetic resonance imaging (MRI), resting-state functional MRI, and immunohistochemistry. Integrated epigenomic, proteomic, and metabolomic profiling of cortical astrocytes isolated 28 days after injury revealed a pronounced metabolic restriction in wild type astrocytes which was remarkably attenuated in the TG2-/- mice. This rescue was associated with a de-repression of gene networks involved in glutamate recycling, lipid metabolism, and metabolic homeostasis. Together, these studies provide novel mechanistic insights into the metabolic dysregulation that characterizes persistent TBI pathology, and establish a foundation for evaluating TG2 as a therapeutic target for TBI.

neuroscience↗

bioRxiv2026

Distinct nigral and brainstem pathology markers map onto separable subthalamic electrophysiological signatures in Parkinson's disease

Subthalamic local field potentials (LFPs) are increasingly used as physiomarkers of the symptomatic state in Parkinsons disease, but their relationship to the underlying neurodegenerative pathology remains unclear. Here, we combined OFF-medication subthalamic LFP recordings with quantitative MRI markers of nigral and brainstem pathology in 33 people with Parkinsons disease. Distinct pathological markers mapped onto dissociable electrophysiological components. Substantia nigra pars compacta susceptibility was associated with increased occupancy, duration and rate of low-{beta} bursts, whereas nigral free water was associated with greater low-frequency aperiodic offset and a steeper slope. Pedunculopontine nucleus free-water- corrected axial diffusivity was selectively associated with high-frequency aperiodic activity, and this relationship strengthened with increasing nigral susceptibility, consistent with dopaminergic-state- dependent influences of extranigral pathology on subthalamic physiology. Only low-frequency aperiodic offset was also associated with contralateral bradykinesia. These findings indicate that the subthalamic LFP is not a unitary readout of dopamine loss or motor state, but an integrated physiological signal in which pathology across interconnected systems is expressed through separable oscillatory and aperiodic components. Chronically implanted devices may therefore provide physiological readouts of underlying disease biology alongside control signals for adaptive therapy.

neuroscience↗

bioRxiv2026

Multimodal neuroimaging-microbiota integration identifies Akkermansia as a modulator of alcohol-induced gut-liver-brain pathology

Alcohol use disorder (AUD) disrupts the gut-liver-brain axis, yet mechanistically grounded and therapeutically actionable targets within this network remain poorly defined. To identify microbial modulators of alcohol-induced tissue pathology, longitudinal advanced diffusion MRI and fecal 16S rRNA profiling were integrated across Marchigian Sardinian alcohol-preferring rats evaluated at baseline, after four weeks of voluntary alcohol intake, and following six weeks of abstinence. Machine learning, specifically random forest models combining neuroimaging and microbiota data, improved phase classification and identified Akkermansia as the microbial feature most strongly associated with alcohol-related white matter microstructural abnormalities. Alcohol exposure induced widespread white matter alterations alongside gut dysbiosis characterized by reduced microbial diversity. To evaluate functional relevance, Akkermansia muciniphila was administered during the abstinence phase. Supplementation with A. muciniphila restored intestinal mucus, reduced liver injury markers, and elevated myelin basic protein levels within affected white matter regions. Collectively, these findings highlight Akkermansia as a critical modulator of alcohol-induced gut-liver-brain pathology and provide experimental support for a causal contribution of specific gut bacteria to persistent white matter damage in AUD. More broadly, this work establishes a robust multimodal framework for microbiome-based target discovery with clear translational relevance for disorders characterized by dysfunction along the gut-liver-brain axis. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAlcohol use disorder (AUD) is associated with gut dysbiosis, impaired intestinal barrier function, liver injury, and persistent white matter abnormalities. Previous studies in patients and animal models have linked alcohol exposure to reduced microbial diversity, altered gut permeability, and white matter microstructural damage, particularly during abstinence. Other work has shown that microbiota-derived interventions can ameliorate peripheral consequences of alcohol exposure, especially in the gut and liver. However, the specific microbial features linked to alcohol-induced brain pathology remain poorly defined, and no prior study has integrated longitudinal microbiota and neuroimaging data to identify candidate microbial modulators of alcohol-related white matter damage and then functionally test them in vivo across the gut-liver-brain axis. Added value of this studyWe developed a multimodal framework that integrates longitudinal advanced diffusion MRI with fecal microbiota profiling and machine learning in alcohol-preferring rats. This approach identified Akkermansia as the microbial feature most strongly associated with alcohol-induced white matter abnormalities. Guided by this result, we administered Akkermansia muciniphila during abstinence and observed coordinated beneficial effects across multiple organs, including restoration of intestinal mucus, reduction of liver injury markers, and recovery of myelin basic protein in affected white matter regions. To our knowledge, this is the first study to combine longitudinal microbiota-MRI integration with experimental validation of a microbiota-based intervention that mitigates alcohol-induced pathology across the gut-liver-brain axis while restoring central white matter integrity. Implications of all the available evidenceOur findings support a mechanistic contribution of specific gut bacteria to persistent alcohol-induced tissue damage and identify Akkermansia as a candidate modulator of gut-liver-brain axis dysfunction in AUD. More broadly, this study establishes a generalizable strategy for integrating microbiota and neuroimaging data to discover biologically meaningful and therapeutically actionable targets in complex disorders involving coordinated peripheral and central pathology.

neuroscience↗

bioRxiv2026

β-Arrestin2 Drives Sex-Specific Akt/GSK3β Signaling, Aβ Pathology, and Cognitive Decline in Alzheimers Disease Mice

Sex is a major determinant of Alzheimers disease risk and progression, yet the molecular mechanisms underlying this dimorphism remain poorly defined, limiting the development of sex-informed therapeutics. {beta}-Arrestin2 is a pervasive, multifunctional regulator common to a host of G protein-coupled receptors (GPCRs) in the brain, but whether it has a sex-dependent role in Alzheimers disease is unknown. Here, we demonstrate that {beta}-arrestin2 deficiency produces sexually dimorphic effects on A{beta} pathology, neuroinflammation, cognition and autophagic flux in APPswe/PS1{Delta}E9 (APP/PS1) mice. In males, Arrb2 deletion reduced A{beta} oligomer burden, enhanced autophagy, suppressed astrocytic and microglial reactivity, and broadly rescued cognition encompassing spatial working memory, spatial learning, cognitive flexibility, and recognition memory. In females, A{beta} pathology and astrogliosis was unchanged and microgliosis was enhanced, with cognitive improvement limited to recognition memory. The male-specific reduction in pathology was accompanied by decreased S473-Akt and S9-GSK3{beta} phosphorylation and enhanced GSK3{beta}/ZBTB16-mediated autophagy, identifying {beta}-arrestin2 as a molecular switch driving sex-restricted A{beta} pathology, glial activation, and cognitive decline in male APP/PS1 mice. These findings identify {beta}- arrestin2 as a sex-dependent node linking A{beta} pathology to cognitive outcomes in males but not females, underscoring the necessity of sex-stratified consideration in the design of GPCR-targeted Alzheimers disease therapeutics.

neuroscience↗

bioRxiv2026

Mesoscale medial temporal lobe connectivity patterns relate to tau pathology and memory in older adults

The medial temporal lobe (MTL) is crucial for episodic memory. Tau pathology is a hallmark of Alzheimer's disease (AD) and accumulates in layer-specific patterns in the MTL during aging. It is, however, unclear whether early AD pathology relates to mesoscale network signatures distinct from non-pathological aging. To address this gap, we acquired 7 Tesla submillimeter-resolution resting-state fMRI, plasma-based AD biomarkers, glial fibrillary acidic protein (GFAP) levels, APOE genotype, regional [18F]PI-2620 tau PET burden, and longitudinal episodic memory data in 75 cognitively unimpaired older adults. Older age was associated with lower perirhinal-hippocampal connectivity and lower network segregation, whereas higher plasma-based AD pathology was associated with higher perirhinal-hippocampal connectivity. Furthermore, temporal-lobe tau burden was related to altered connectivity patterns in tau-vulnerable MTL subfields and layers, dependent on GFAP levels. Retrosplenial tau burden was associated with higher hippocampal-retrosplenial connectivity consistent with tau spread along canonical hippocampal output pathways. Finally, higher connectivity within the hippocampus attenuated the negative association between temporal-lobe tau burden and memory performance but predicted unfavorable memory trajectories. Our findings show differential associations of age and AD pathology with mesoscale MTL-connectivity patterns. Importantly, increased hippocampal connectivity may support memory function in the short term while contributing to subsequent memory decline.

neuroscience↗

bioRxiv2026

Complement component C4 regulates amyloid pathology and glial reactivity in mouse model of Alzheimer's Disease

The complement system, a proteolytic cascade crucial for innate immune system function, is dysregulated in brain aging and neurodegenerative diseases, including Alzheimer Disease (AD). In models of AD, complement proteins, including C1q and C3, are upregulated and mediate microglial clearance of amyloid plaques and pruning of synapses. Among complement genes, C4b, which in mice encodes complement protein C4, is the most highly upregulated in astrocytes in the setting of aging and amyloid pathology. While C4 plays a key role in the complement cascade, there have been no investigations of the direct role of C4 in regulating AD pathology. To probe the function of C4 in amyloid plaque-related pathology, we crossed a germ line C4b knockout mouse (C4 KO) to the 5XFAD mouse model of AD-related amyloidosis. To our surprise, we observed striking reductions in amyloid plaque pathology across multiple brain regions in 5XFAD-C4 KO mice relative to standard 5XFAD controls. This reduction in plaque burden stands in sharp contrast to previous reports of C3 deletion in AD models, which increases plaques. Additionally, we observed a reduction in neuroinflammation and peri-plaque glial clustering in 5XFAD-C4 KO mice, suggestive of a role for C4 in regulating overall neuroinflammatory tone in AD. Finally, we observed a phenotypic shift of the peri-plaque microglia to a more reactive disease-associated microglia (DAM) phenotype, indicating that C4 could be an important factor in regulating microglial reactivity in AD. Altogether, our results demonstrate that C4 may have functions beyond the classical complement cascade and may serve as a key facilitator of AD-related glial function and pathology and a possible target for therapeutic modification.

neuroscience↗

bioRxiv2026

Spatial proximity to AD pathology defines cell-type and genotype-specific characteristics in human AD hippocampus

How amyloid-{beta} (A{beta}) plaques and tau phosphorylation spatially relate to cell response and genetic variation in Alzheimer's disease (AD) brain is currently unclear. We established a pipeline to concurrently annotate A{beta} and AT8 ptau pathology and cell-specific MERFISH expression profiles in human control and AD hippocampus. We characterized expression signatures in glia and neurons proximal or distal to A{beta} plaques, AT8 ptau-enriched neurons, or A{beta} and AT8 ptau in combination, and used spatially-defined transcriptional signatures to infer pathology-associated states in large snRNA-seq datasets lacking spatial context. We characterized variants from 120 gene loci associated with AD risk that affect cell-specific gene expression within local pathological contexts. Astrocyte APOE4/E4 expression was specifically suppressed in proximity to A{beta} plaques, whereas other APOE genotypes were unaffected by A{beta} proximity. Together, this analysis pipeline couples expression profiles in proximity to A{beta} and tau pathology, and implicates AD cis-gene variants with spatial sensitivity to AD pathology.

neuroscience↗

bioRxiv2026

Neuroinflammation is an early pathological process in a mouse model of prodromal Parkinsons disease

Approximately 90% of Parkinson's disease (PD) patients exhibit olfactory deficits, which often precedes motor symptoms by years, and are a robust predictor for PD and subsequent cognitive decline. Pathological changes in the PD olfactory system, particularly synuclein (Syn) pathology in the olfactory bulb (OB) and severe involvement of the anterior olfactory nucleus (AON), are distinct from normal aging. However, the causal link between Syn aggregation and functional impairment, potentially involving cytotoxicity and neuroinflammation, remains elusive. To investigate these early pathological events, we utilized a prodromal PD model that we have previously characterized, involving the unilateral OB injection of Syn preformed fibrils (PFF) in wild-type mice. This triggers the transneuronal spread of pathogenic Syn, and olfactory dysfunction starting at 1-month post-injections. Here we report on neuropathological and inflammatory events 1-3 month following injection of PFFs into the OB. Following PFF injection, Syn pSer129 pathology progressively accumulated bilaterally in the AON and ipsilateral in the piriform cortex (PCX) over three months. Stereological quantification revealed no significant neuronal loss in the AON or PCX during this 1-3 month interval, indicating that olfactory impairment precedes overt neurodegeneration. Instead, we identified the upregulation of pro-inflammatory genes (Il-1{beta} ; and Il-6), significant microglial reactivity, and sustained astrogliosis within olfactory structures. These findings identify neuroinflammation as a key early mediator linking Syn pathology to olfactory dysfunction in the absence of neuronal loss. This suggests a critical window for therapeutic intervention and highlights neuroinflammatory markers as potential biomarkers for the prodromal phase of PD.

neuroscience↗

bioRxiv2016

Using Machine Learning to Parse Breast Pathology Reports

1PurposeExtracting information from Electronic Medical Record is a time-consuming and expensive process when done manually. Rule-based and machine learning techniques are two approaches to solving this problem. In this study, we trained a machine learning model on pathology reports to extract pertinent tumor characteristics, which enabled us to create a large database of attribute searchable pathology reports. This database can be used to identify cohorts of patients with characteristics of interest.\n\nMethodsWe collected a total of 91,505 breast pathology reports from three Partners hospitals: Massachusetts General Hospital (MGH), Brigham and Womens Hospital (BWH), and Newton-Wellesley Hospital (NWH), covering the period from 1978 to 2016. We trained our system with annotations from two datasets, consisting of 6,295 and 10,841 manually annotated reports. The system extracts 20 separate categories of information, including atypia types and various tumor characteristics such as receptors. We also report a learning curve analysis to show how much annotation our model needs to perform reasonably.\n\nResultsThe model accuracy was tested on 500 reports that did not overlap with the training set. The model achieved accuracy of 90% for correctly parsing all carcinoma and atypia categories for a given patient. The average accuracy for individual categories was 97%. Using this classifier, we created a database of 91,505 parsed pathology reports.\n\nConclusionsOur learning curve analysis shows that the model can achieve reasonable results even when trained on a few annotations. We developed a user-friendly interface to the database that allows physicians to easily identify patients with target characteristics and export the matching cohort. This model has the potential to reduce the effort required for analyzing large amounts of data from medical records, and to minimize the cost and time required to glean scientific insight from this data.

Pathology↗