Biology subjects

Lee, D.

Publications and source records attributed to Lee, D..

At least 19 recordsLinked to original sources

bioRxiv2026

Survival-associated cellular communication networks in human solid cancers

Single-cell atlases have enabled the prediction of human cell-cell communication (CCC) networks in cancer, but whether predicted communication networks have clinical significance is not well understood. Here, we integrated a pan-solid cancer scRNA-seq atlas comprising 78 cell types from 318,426 quality-controlled cells with bulk RNA-seq and clinical outcome data from The Cancer Genome Atlas (TCGA) to develop Single-cell-based Kaplan-Meier Analysis Network (SKyNet). SKyNet prioritizes ligand-receptor interactions associated with overall survival across 11 human solid cancers, predicting unique interactions not inferred by previous CCC algorithms. In pancreatic adenocarcinoma, SKyNet-predicted endothelial-pericyte interactions were associated with poor outcomes that were validated by independent spatial transcriptomics and survival cohorts. In lung adenocarcinoma, lymphatic endothelial cell interactions consisting of collagen-integrin pairs were associated with poorer survival outcomes. In kidney renal clear cell carcinoma and kidney renal papillary cell carcinoma, fibroblast communication networks displayed disparate survival associations, with the DSC2-DSG2 axis associated with better survival outcomes. Thus, SKyNet provides a hypothesis-generating framework for cell type-specific communication pathways associated with patient outcomes.

systems biology↗

bioRxiv2026

Transcriptomic reconstruction of an interregional molecular connectome in schizophrenia

Background: Schizophrenia is increasingly viewed as a disorder of multi-regional brain networks, but molecular and pathophysiological hypotheses are often studied at the level of single brain regions or neurotransmitter systems. A multi-regional, multi-neurotransmitter analysis is needed to clarify how molecular abnormalities relate to circuit-level hypotheses of the disorder. Methods: Transcriptomic data from 2,209 post-mortem brain samples spanning five brain regions in 1,037 individuals were integrated. Directed connectivity strengths between regions were estimated using co-expression between presynaptic and postsynaptic neurotransmission-related genes. These estimates constitute an "interregional molecular connectome". Macaque transcriptomic data were used to benchmark the estimation pipeline against reference macaque connectomes. Connectivity differences between healthy controls and patients with schizophrenia were calculated, and a directional consistency filter was applied to identify candidate dysregulations. An LLM-augmented literature screening framework was used to assess the level of literature support for our candidates. Results: Our estimation pipeline showed concordance with reference connectomes, outperformed whole-transcriptome and random-gene co-expression measures, and remained stable when applied to macaque data. A total of 10 connections were marked as candidate dysregulations in schizophrenia at a nominal permutation threshold. Three of the candidates align with established anatomical connectivity, and another three with anatomical connections through relay regions. These candidates were characterized by bidirectional abnormalities in the cortico-striatal circuitry. The remaining four candidates had no well-established monosynaptic connection between two regions. These candidates were interpreted as co-regulated co-expression coordination changes. Literature screening quantified the number of articles discussing each candidate and how many of the articles directly support or refute each candidate. Our candidates collectively highlight the role of the cortico-striato-thalamo-cortical circuit in the pathophysiology of schizophrenia. Conclusions: Interregional co-expression of neurotransmission-related genes carries more anatomical information than whole-transcriptome co-expression. Applied to schizophrenia, our analysis recapitulates known hypotheses and also proposes hypothesis-generating data-driven findings for experimental follow-up. This approach complements conventional region-wise analyses. Our approach could support a unified, multi-regional, and multi-neurotransmitter perspective of schizophrenia and point to candidate molecular mechanisms for further studies.

bioinformatics↗

bioRxiv2026

Blood-brain barrier-traversing multivalent TGFβ trap for anti-cancer immunomodulation of gliomas

Clinical studies have revealed that glioblastoma (GBM) is refractory to immunotherapy, such as immune checkpoint inhibitors (ICIs), due to the immunosuppressive tumor microenvironment (TME) primarily intensified by intratumoral upregulation of transforming growth factor-{beta} (TGF{beta}). Primary GBM tumor bulks are surgically removed in clinic, but invasive tumor cells infiltrated into surrounding normal brain tissue cannot be eradicated by systemic therapy due to the integral blood-brain barrier (BBB), leading to near-inevitable tumor recurrence. To address these translational challenges, we have engineered a TGF{beta}-inhibiting protein nanocage comprising human heavy-chain ferritin protein and TGF{beta} receptor II ectodomain that enables BBB penetration and multivalent TGF{beta} entrapment, respectively. We demonstrate that the nanocage platform, denoted T{beta}R2-HFt, following systemic administration, traverses the BBB, and extensively modulates immunosuppressive TME, both stromal and immune components, thereby potentiating the therapeutic efficacy of a clinically used ICI in multiple mouse glioma models. Notably, a majority of the glioma-bearing animals that received surgical tumor resection, followed by treatment with T{beta}R2-HFt and the ICI, survived the tumor and resisted tumor rechallenge, providing a potential means to control GBM in a durable manner.

bioengineering↗

bioRxiv2026

Kidzoi Enables Cell-Type-Specific Regulatory Activity and Variant Effect Prediction in Kidney

Sequence-to-function (S2F) deep learning models predict genome-wide functional profiles directly from DNA sequences and have significantly advanced our understanding of gene regulation. However, existing S2F models are fundamentally constrained by their initial training datasets, and no single model encompasses the full spectrum of cell types, clinical conditions, and cellular states, while training new models de novo is nontrivial. Here, we develop Kidzoi, a kidney cell-type-specific S2F model obtained by transfer learning from the pretrained model Borzoi using single-nucleus chromatin accessibility data from human kidney tissue. Kidzoi accurately predicts cell-type-specific chromatin accessibility and improves regulatory variant effect prediction by 10-23% over existing models. Furthermore, Kidzoi effectively prioritizes genome-wide association study (GWAS) fine-mapped causal variants associated with kidney function (estimated glomerular filtration rate based on both creatinine and cystatin C; eGFRcr-cys) while resolving their cell-type specificity. Systematic ablation of flanking sequence indicates that a local context of 32-64kbp, representing only 6-12% of the full model input, is sufficient for accurate variant effect prediction. Finally, we show that a multi-task model achieves comparable performance to single-task models at a substantially reduced computational cost.

bioinformatics↗

bioRxiv2026

StaBLE: digital metrics capture balance performance across a wide spectrum of balance tasks and abilities

Balance is fundamental to mobility and independence, yet it remains difficult to measure in a way that is both clinically meaningful and feasible for widespread adoption. There is a need for more quantitative, objective, and accessible balance assessments. To this end, we created the Stanford Balance Level Evaluation (StaBLE), a battery of 18 balance-challenging tasks and accompanying digital performance metrics computed from video that aimed to capture widely ranging balance abilities across 180 participants. We validated the StaBLE score against existing clinical scales and found that it correlated with age ({rho} = -0.76, p<0.001), the Activities-Specific Balance Confidence Scale ({rho} = 0.60, p<0.001), a Mini-Balance Evaluation Systems Test task ({tau}=0.55, p<0.001), 4-Stage Balance Test ({tau} = 0.55, p<0.001), and Short Physical Performance Battery ({tau} =0.57, p<0.001). StaBLE overcame ceiling effects in these existing scales and had a different underlying distribution for those identified at risk of falling and not (KS: 0.67, p<0.001). To reduce the time it takes to perform the test, we identified subsets of balance tasks that best predicted the StaBLE score across different populations. Together, our dataset, balance assessment protocol, and performance-based score demonstrate the validity of digital measures of balance.

bioengineering↗

bioRxiv2026

Single-Cell Study Designs Are Systematically Underpowered for Small-Effect Genes

Single cell differential expression analysis enables biologists to make statistical conclusions about which genes are up or downregulated in a particular cell type, between two conditions, such as those with or without a disease. However, due to biological and technical noise, these differences are hard to detect reliably. Determining if an experiment has sufficient power is often derived from simulations or small pilot samples, if done at all. Here, we use sex-biased differential expression on 1,494 donors in three brain cell types to derive empirically grounded power estimates for a variety of experimental setups. Our work reveals a substantial lack of power for reliably detecting the small effects in the range that many studies report, even in experiments containing 600 donors. When reducing the astrocyte data to the poor sequencing characteristics of microglia, over half the differentially expressed genes (DEGs) detected in the full set were lost, highlighting the damage caused by insufficient sequencing depth and cell counts. Despite standard thresholds of adjusted p-value with multiple testing correction, only the top quartile of significant genes were reproducible. Furthermore, from fitting a predictive model to the empirical outcomes, we find cell count and expression levels of genes to be a strong determinant of power. As such, we advocate for future studies to employ cell type enrichment and deeper sequencing, especially for rarer populations like microglia, emphasise the importance of powering experiments of this type when seeking robust findings, and suggest stricter significance thresholds for future discoveries.

genomics↗

bioRxiv2026

Acute head shaking precedes chronic corpus callosum deficits during repeated cocaine exposure in common marmosets

Background: Stimulant exposure can induce acute stereotyped behaviors and chronic alterations in brain connectivity and white matter integrity. However, the temporal sequence and molecular changes linking these cocaine-induced phenotypes remain unclear. Methods: We combined LabGym-based behavioral analysis, longitudinal brain imaging, and cross-species molecular analysis in 11 common marmosets (Callithrix jacchus; seven male, four female): four underwent behavioral and imaging studies, six provided molecular data, and one provided immunohistochemical data. Male Cryab knockout and wild-type mice underwent functional studies. Results: Acute cocaine (5 mg/kg, intraperitoneally) induced rapid, repetitive lateral head movements, defined as head shaking. After 1 and 10 months of repeated exposure, resting-state functional connectivity was altered in sensory, parietal, prefrontal, motor, and hippocampal regions. Changes were detected at 1 month, whereas diffusion tensor imaging showed reduced fractional anisotropy and axial diffusivity in the corpus callosum splenium at 10 months, with no significant genu changes. Cross-species transcriptomic and proteomic comparison identified DPYSL2 and DNM3 as shared axon-associated molecules. Western blotting showed reduced DPYSL2 in brain tissue from cocaine-treated marmosets. CRYAB localized to O4-positive callosal oligodendrocytes and increased following chronic cocaine exposure. Cryab knockout mice had reduced corpus callosum thickness, increased forced-swim immobility, and reduced open-field distance traveled, supporting a role for CRYAB in corpus callosum integrity and depression-related behavior. Conclusions: These findings show that acute cocaine-induced stereotyped head shaking precedes functional connectivity changes and later corpus callosum deficits. Reduced DPYSL2 may be associated with axonal dysfunction, whereas increased CRYAB may represent a response to cocaine-induced white matter stress.

pharmacology and toxicology↗

bioRxiv2026

Temporal niche partitioning through olfactory cell type evolution

Temporal niche partitioning enables species to use the same resource at different times, but the underlying mechanisms are unknown. We show that Drosophila sechellia, a specialist on Morinda citrifolia noni, exhibits narrow temporal preference for the most toxic, ripe fruit, reducing exposure to competition, parasitization and microbial infection that can occur on other stages. Chemical analysis highlighted ketones as signature odors of ripe noni. Comparative single-cell transcriptomic atlases revealed that D. sechellia has co-opted expression of a larval ketone receptor, Or45a, in an adult olfactory neuron population. The novel expression of Or45a can be ascribed solely to cis-regulatory changes and is sufficient to confer physiological sensitivity to ripe noni. Importantly, Or45a is required for D. sechellia's ripe noni preference, acting redundantly with a second ketone receptor, Or85c/b, whose neuron population has expanded in D. sechellia. Our results provide an unprecedented link between cell type evolution and ecologically-advantageous, temporal niche partitioning.

neuroscience↗

bioRxiv2026

Restoration of circulating 2-arachidonoylglycerol levels attenuates cocaine self-administration through endocannabinoid-dopamine interactions in common marmosets

To date, no pharmacotherapy has been approved for cocaine use disorder. Endocannabinoid signaling is closely related to dopamine-dependent reinforcement and may regulate cocaine-related behaviors. In this study, we used common marmosets (Callithrix jacchus) to investigate whether 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid lipid, reduces cocaine reinforcement in a non-restraint oral self-administration model. Marmosets performed oral cocaine self-administration under a fixed-ratio 1 schedule, and cocaine intake was confirmed using plasma benzoylecgonine detection. Dopamine transporter (DAT)-related positron emission tomography (PET) signal, DAT and G protein-coupled receptor 55 (GPR55)-associated fluorescent signals, GPR55/DAT immunofluorescence, and synaptosomal dopamine responses were assessed using 18F-N-(3-fluoropropyl)-2{beta}-carboxymethoxy-3{beta}-(4-iodophenyl) nortropane (18F-FP-CIT) PET imaging, ex vivo fluorescent ligand imaging, confocal microscopy, and dopamine quantification. Marmosets acquired oral cocaine self-administration with preferential active lever responding. Repeated cocaine self-administration reduced striatal DAT-related 18F-FP-CIT PET signal in vivo. In striatal slices, cocaine decreased fluorescent false neurotransmitter (FFN102)-associated DAT signal and increased T1117-associated GPR55 signal. Systemic 2-AG pretreatment reduced cocaine self-administration while restoring diminished circulating 2-AG levels. GPR55 and DAT immunofluorescent signals were colocalized in marmoset brain sections, and 2-AG enhanced cocaine-induced dopamine elevation in synaptosomal preparations. Taken together, these findings suggest that 2-AG attenuates cocaine-taking behavior and may be associated with GPR55/DAT-related dopaminergic responses in common marmosets.

pharmacology and toxicology↗

bioRxiv2026

AI-driven framework modeling perturbation in brain organoids reveals candidate genes for autism

Autism gene discovery is constrained by the rarity and heterogeneity of damaging variants, requiring large cohorts to identify susceptibility genes. Neural organoids and single-cell foundation models enable perturbation modeling in neurodevelopmental contexts. Here, we show that perturbation-informed foundation modeling of neural organoids can provide functional context for prioritizing candidate genes with genomic and clinical support. We constructed a 3.6-million-cell organoid atlas and trained models to predict genome-wide perturbation responses. Benchmarking 17 models identified a telencephalic neuron-specific model best preserving autism-relevant perturbation structure. Genome-wide profiling revealed two clusters associated with mid-fetal synaptic neuronal processes and early radial glia ubiquitin signaling. These clusters were supported by damaging-variant enrichment and clinical phenotypes across 89,916 family-based samples. Logistic-regression prioritization identified 343 candidates, including 167 in the key clusters, with convergence across TADA signals and recurrent evidence for NBEA and KLHDC10. This framework integrates predicted perturbation effects with genomic evidence to support autism candidate prioritization.

bioinformatics↗

bioRxiv2026

Intrauterine growth restriction is associated with adaptive hematopoietic reprogramming and selective immune rewiring in monozygotic twins

BackgroundPrenatal growth restriction has been associated with adverse neonatal and long- term health outcomes, yet the epigenetic mechanisms by which an adverse intrauterine environment shapes fetal immune development remain incompletely understood. Monozygotic dichorionic-diamniotic twins with selective fetal growth restriction (sFGR) provide a unique human model for investigating environmentally driven developmental programming independent of genetic variation and inter-twin placental vascular anastomoses. MethodsUmbilical cord blood buffy coat samples were collected from three sFGR and two gestational age-matched concordant control twin pairs. Bulk RNA sequencing and genome-wide DNA methylation analysis were performed, followed by differential expression, pathway enrichment, hematopoietic and immune module analyses, differential methylation, and integrative transcriptomic-epigenomic analyses. ResultsCompared with concordant control twin pairs, discordant twins exhibited broad attenuation of immune and inflammatory transcriptional programs alongside enrichment of erythroid- and hypoxia-related pathways, consistent with adaptive hematopoietic responses to intrauterine stress. Within discordant twin pairs, the growth-restricted co-twins displayed marked transcriptional asymmetry characterized by selective enrichment of cytotoxic lymphoid signatures despite global suppression of myeloid and antigen-presenting cell-associated programs. Integrated transcriptomic and epigenomic analyses further revealed coordinated epigenetic remodeling, with hypomethylated regions in growth-restricted twins enriched for immune regulatory pathways, including T cell differentiation and leukocyte activation. At selected loci, concordant hypomethylation and increased gene expression suggested a potential epigenetic basis for the observed immune remodeling. ConclusionsThese findings suggest that intrauterine growth restriction is associated with coordinated hematopoietic and immune reprogramming at birth, consistent with both compositional and cell-intrinsic alterations. In genetically identical twins, relative growth divergence was associated with polarized transcriptional states, highlighting how intrauterine environmental differences may shape early immune development independent of genetic background.

genomics↗

bioRxiv2026

Exercise engages a mechanically activated astrocyte state linking muscle activity to hippocampal plasticity

Physical exercise promotes brain health in part through muscle-derived factors that enter the brain, but how peripheral signals are translated into neural responses remain unclear. Here, we identify astrocyte contraction as a previously unrecognized physiological response to exercise signals that may contribute to adult hippocampal neurogenesis. In vivo, voluntary running rapidly induced nuclear localization of the mechanically sensitive transcriptional regulator Yes-associated protein (YAP), and increased non-muscle myosin II phosphorylation in hilar astrocytes in mice, consistent with acute contraction. Using an in vitro platform with ultrasensitive force sensors, we found that factors released by contracting skeletal muscles activated astrocytes which in turn increased contraction that was necessary and sufficient for their proliferation and expansion. Activated astrocytes subsequently released soluble factors that modulated neuronal network tension and promoted immature neuron abundance. These findings identify astrocyte contractility as a physiological transducer of exercise-derived muscle signals and establish cellular force generation as a potential mechanism regulating neuroplasticity.

neuroscience↗

bioRxiv2026

A lipid nanoparticle platform for high yield CRISPR-targeted homology directed repair enables fully non-viral CAR T cell generation

CRISPR-mediated homology directed repair (HDR) enables targeted CAR integration with improved fitness and therapeutic potential of CAR T cells. However, current methods for generating HDR-engineered CAR T cells rely on viral transduction or electroporation, approaches that limit global implementation and constrain patient access due to their cost, toxicity, and requirement for centralized manufacturing. Through a screen of ionizable lipids, we identified LNP systems that enable CRISPR-mediated gene knock-in (KI) in primary human T cells and are amenable to hand mixing by ethanol injection as a research tool or machine formulation for larger scale manufacturing. Modifying the linear dsDNA HDR template with truncated Cas9 target sequences (tCTS) enhanced HDR rates across multiple LNP systems. We optimized two LNP formulations capable of HDR-mediated KI of a large 4kB CD19 CAR-EGFR HDR template into the TRAC locus with rates of [≥]8% and >10x improved edited cell yields compared to electroporation. We demonstrate that LNP-generated CAR T cells exhibited similar growth kinetics, activation states, differentiation states, and killing capacity compared to electroporation-generated CAR T cells. Our LNP platform components are fully disclosed, commercially sourced, and enable efficient fully non-viral CRISPR-HDR cell engineering across diverse applications.

bioengineering↗

bioRxiv2026

Behavioural and neural mechanisms for stochastic choices in mixed strategy games

Adaptive behaviour usually requires exploiting regularities in the environment, but in competitive settings the opposite can be true: predictable choice patterns can be exploited by others, making unpredictability itself advantageous. How neural circuits generate such strategic variability remains poorly understood. Here, we trained mice to play a zero-sum game against an opponent that exploited statistical regularities in their choices and rewards, and tracked their behaviour and dorsal cortical dynamics across learning. Using a hidden Markov model, we found that mice transitioned from structured, predictable strategies towards a near-optimal stochastic strategy as they learned. Applying the same framework to monkeys playing the same game identified a shared stochastic strategy across species, despite differences in how it was deployed. Cortex-wide imaging revealed that stochastic choices were associated with reduced representation of reward history, while immediate reward signals remained robust. Critically, while the strength of cortical reward signals predicted subsequent choice during reward-guided behaviour, this relationship was abolished during stochastic behaviour. Thus, adaptive stochasticity does not simply arise from a loss of reward information, but from selectively decoupling reward from future choice. These results reveal a neural mechanism through which animals suppress otherwise useful reward-guided structure to generate adaptive unpredictability in competitive environments.

neuroscience↗

bioRxiv2026

Synaptic input-selective homeostasis safeguards developing cortical neurons toward setpoint activity

Homeostatic plasticity stabilizes brain function by maintaining neuronal activity around a setpoint. Although homeostatic mechanisms are well characterized in mature circuits, it remains unknown how developing neurons, which progress from near silence at birth to sustained activity, establish and safeguard their setpoint activity levels against perturbations. Here we show that activity setpoints are intrinsic properties of neuronal identity actively achieved by cell-autonomous, targeted synaptic remodeling during development. Cortical layer 2/3 pyramidal cells were sparsely silenced from their birth by overexpressing the inward-rectifier potassium channel Kir2.1 to chronically suppress their excitability. These Kir2.1-expressing neurons, however, progressively overcame this perturbation during postnatal development and ultimately reached the activity levels comparable to neighboring control neurons. This recovery was accompanied by enhanced synaptic excitation and reduced inhibition that did not follow the classical global multiplicative synaptic scaling. Instead, excitation from infragranular layers, rather than layer 4 and layer 2/3, was selectively strengthened through increasing quantal amplitudes and unsilencing silent synapses that required the insertion of GluA2-containing AMPA receptors. Inhibition recruited by excitatory inputs was selectively reduced at specific pathways. These results identify a synaptic input-selective homeostatic program enabling cortical neurons to reach activity setpoints, revealing a new mechanism contributing to neurodevelopmental robustness.

neuroscience↗

bioRxiv2026

Synaptic engram underlies memory

Memory encoding cells, or engram cells, are sparsely distributed across the brain. Recent findings have shown that memory formation coincides with the strengthening of interregional synaptic connectivity between engram ensembles. However, whether this learning-induced synaptic reorganization causally supports memory, independently or in concert with heterosynaptic and intrinsic plasticity, remains elusive. Here we developed optically implemented spike-timing-dependent plasticity (oSTDP), which induces synaptic depression selectively at target synapses by controlling the relative timing of pre- and postsynaptic activity. In vivo application of oSTDP to the synapses between entorhinal cortex (EC) and dentate gyrus (DG) engram cells caused a significant synaptic depression and the resultant memory impairment. Our results demonstrate that plasticity of functional connectivity between memory-encoding ensembles causally underlies memory.

neuroscience↗

bioRxiv2026

An immune-stimulating antibody conjugate spatiotemporally targeting CD47 and TLR9 elicits macrophage-dependent tumor clearance and durable anti-cancer adaptive immunity

Cluster of differentiation 47 (CD47) blockade promotes tumor cell phagocytosis; however, transitioning this initial innate immune event into durable anti-cancer adaptive immunity and tumor control remains a critical challenge. To address this translational gap, we have engineered aCD47 - CpG, a novel immune-stimulating antibody conjugate (ISAC) coupling a CD47-blocking antibody (aCD47) to a Toll-like receptor 9 agonist, unmethylated CpG, to enable synchronized deployment of co-stimulatory signals during tumor engulfment. This ISAC, aCD47-CpG, but not the parent aCD47, reprograms macrophages toward an anti-tumor M1-like phenotype, enhances antigen cross-presentation, and promotes robust CD8+ T cell priming. We found that systemically administered aCD47-CpG drove macrophage-dependent tumor suppression in a human lymphoma xenograft model. In parallel, the treatment in immunocompetent syngeneic models of lymphoma and highly immunosuppressive triple-negative breast cancer resulted in profound tumor regression, metastasis inhibition, and durable anti-cancer immune memory. These effects were accompanied by remodeling of the immunosuppressive tumor microenvironment toward an immune-permissive state, characterized by M2-to-M1 macrophage repolarization, intratumoral infiltration of cytotoxic and memory T cells, and depletion of regulatory T cells. This spatiotemporally coordinated immunotherapy platform offers a promising strategy to bridge innate and adaptive immunity, thereby advancing the translational potential of CD47-targeted cancer therapies.

cancer biology↗

bioRxiv2026

Progranulin haploinsufficiency remodels the cerebral microvasculature and neurovascular unit

Progranulin (PGRN) deficiency is a major genetic cause of frontotemporal dementia (FTD), yet its impact on cerebrovascular function remains understudied. Here, we show that PGRN deficiency contributes to cerebral microvascular perfusion and induces alterations within the neurovascular unit. In vivo two-photon imaging revealed increased capillary stalling and in cerebral blood flow (CBF), driven in part by increased leucocyte-capillary interactions and elevated endothelial ICAM-1 expression. Transcriptomic profiling of isolated cerebral microvessels demonstrated coordinated upregulation of immune and extracellular matrix pathways alongside suppression of angiogenic and stress-response programs, indicative of endothelial activation. Cross-species analyses identified partial conservation of these vascular signatures in endothelial cells from human FTD-GRN patients, associated with dysregulated angiogenic and inflammatory signaling. Despite altered tight junction organization and reduced solute carrier transporter expression, blood-brain barrier (BBB) permeability remained largely intact, suggesting functional rather than structural BBB disruption, as well as. These vascular changes were accompanied by broad alterations in the morphology of astrocytes, pericytes, and microglial cells. Here we determined a novel role for progranulin in cerebrovascular homeostasis and established microvascular dysfunction as a key driver of FTD-GRN pathophysiology.

neuroscience↗