Biology subjects

Gan, L.

Publications and source records attributed to Gan, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Development of an HK-fbp1-based vaccine platform against Cryptococcus neoformans

Cryptococcal meningitis remains a leading cause of death among HIV/AIDS patients, and no antifungal vaccine is available in clinical use. We previously showed that mice immunized with a heat-killed preparation of Cryptococcus neoformans (Cn) fbp1{Delta} mutant (HK-fbp1) are protected against cryptococcosis and other invasive mycoses, suggesting that HK-fbp1 is an intriguing vaccine candidate for further study. Recent studies have reported that heat-killed wild type H99 (HK-H99) can also offer some protection in other vaccination models. Here we set out to decipher the differential protective capacity of HK-fbp1 versus HK-H99 across multiple conditions. We observed that HK-fbp1 confers superior protection in both prophylactic and therapeutic intranasal immunization settings than HK-H99, which was associated with greater activation of pulmonary CD4+ T cells and stronger airway IFN-{gamma} production. In addition, HK-fbp1 preparations were highly stable, retaining full protective efficacy even after 5 years of frozen storage. Mice intranasally immunized with two-dose HK-fbp1 were protected against challenge by up to 106 H99 cells, a 100-fold increase over the commonly used lethal inoculum. Addition of a CpG adjuvant ODN to HK-fbp1 (HK-bp1/ODN) led to a 5-fold reduction of the intranasal vaccine inoculum required for protection, and its single-dose intramuscular vaccination induced protection persisted for at least 3 months post vaccination. Together, these findings highlight the robust protective capacity and formulation versatility of HK-fbp1, supporting its further development as a stable, dose-sparing antifungal vaccine candidate.

microbiology↗

bioRxiv2026

ALS/FTD-linked TDP-43 alterations prevent HSV-1 infection by disrupting cell-adhesion pathways

TAR DNA-binding protein-43 (TDP-43) alterations are a key hallmark of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative disorders. Increasing evidence links these conditions to viral infections, but it is not known if and how viral pathogens may be affected by disease-associated TDP-43. We found that ALS/FTD-linked forms of human TDP-43 prevent infection by herpes simplex virus type-1 (HSV-1), a common neurotropic virus. This cell-autonomous protective effect was conserved across different TDP-43 mutations, sporadic ALS, and C9ORF72-ALS, in neural and non-neural cell types, and in patient-derived cells and animal models. In addition to restricting infection, TDP-43 mutation prevented inflammatory and cell stress-related responses to HSV-1 exposure. TDP-43 knockdown but not overexpression was sufficient to protect cells from HSV-1 infection, implicating a loss-of-function mechanism. Neurons with TDP-43 mutation had disruptions in adhesion-related pathways and, accordingly, had reduced early-stage viral binding and entry. Further analyses revealed alternative RNA splicing and impairment of focal adhesion kinase (FAK/PTK2), a key mediator of cell-adhesion pathways. Inhibition of FAK was sufficient to decrease HSV-1 infection, and genetic enhancement of functional but not inactive FAK promoted infectivity in cells with TDP-43 mutation. Together, these data indicate that TDP-43 affects virus-host interactions by influencing adhesion pathways required for viral infection.

neuroscience↗

bioRxiv2026

Circulating apoB-containing lipoproteins constituted blood-borne innate immune barrier limits ZIKV dissemination and congenital infection risk

Following establishment of primary viremia, flaviviruses require prompt penetration through vascular endothelium to achieve systemic dissemination, yet most infections remain asymptomatic or self-limited. Canonical defenses, including complement and phagocyte clearance, cannot fully explain this containment, suggesting an additional blood-borne antiviral barrier. Here, we identify apoB containing lipoproteins as potent restriction factors against Zika virus (ZIKV), a devastating danger of global pregnancy. By displaying surface accessible phosphatidylserine (PS), they competitively occupy host PS receptors and block entry by viruses exploiting apoptotic mimicry, including flaviviruses, Ebola, and chikungunya virus. In vivo, increasing apoB lipoproteins enhances serum antiviral activity and limits systemic ZIKV dissemination. This barrier extends to the maternal fetal interface, where elevated maternal LDL attenuates vertical transmission and fetal abnormalities. Its efficacy is modulated by gestational fluctuations in maternal LDL level and low abundance in fetal circulating LDL. Collectively, apoB containing lipoproteins form a constitutive blood-borne innate immune barrier that restrains apoptotic-mimicry viruses during the intravascular phase, limits viral dissemination and reduces congenital infection risk. This study provides a rationale for developing diet augmentation strategy to strengthen this innate barrier in at-risk individuals.

microbiology↗

bioRxiv2026

A lenvatinib-resistance-derived transcriptional program identifies metabolic identity remodeling associated with unfavorable survival in hepatocellular carcinoma

Background: Metabolic adaptation is a recognized feature of therapeutic resistance in hepatocellular carcinoma (HCC), but it is unclear whether transcriptional states exposed during acquired resistance are restricted to drug adaptation or reflect broader aggressive tumor biology. We tested whether metabolic programs derived from a lenvatinib-resistance model identify a clinically adverse transcriptional state in an independent HCC patient cohort. Methods: The discovery framework was based on GSE186191, comprising parental and acquired lenvatinib-resistant Hep3B and Huh7 cells. A pre-specified 33-gene lipid-source ledger served as a biological anchor, and three discovery-derived programs, MYC Targets V2, mTORC1 Signaling, and Fatty Acid Metabolism, were frozen before patient-level evaluation. In TCGA-LIHC, single-sample enrichment scores for the three programs were population-standardized and summed to generate an integrated metabolic score. Overall survival was assessed by Kaplan-Meier and Cox analyses. Whole-transcriptome differences between high- and low-score tumors were characterized by preranked gene set enrichment analysis (GSEA). Results: The survival cohort comprised 282 patients (118 deaths), with 141 patients in each median-defined score group. High-score patients had shorter overall survival (log-rank P=0.000419). The continuous score was associated with mortality in univariable analysis (HR 1.86, 95% CI 1.33-2.61; P=0.000293) and in the frozen model adjusted for age, sex, and stage indicators (HR 1.93, 95% CI 1.35-2.76; P=0.000350; n=277). In 327 primary tumors, Fatty Acid Metabolism was strongly depleted in high-score tumors (NES -2.06; FDR<0.001). MYC Targets V2 (NES 1.18; FDR=0.232) and mTORC1 Signaling (NES 1.11; FDR=0.229) showed positive directional enrichment without FDR significance. Conclusions: A lenvatinib-resistance-derived transcriptional program is associated with an adverse-survival state in HCC. The strongest patient-level pathway feature is depletion of canonical fatty-acid metabolism, accompanied by directional MYC/mTORC1 features rather than statistically established pathway activation. These findings support a testable model of metabolic identity remodeling but do not establish causality or clinical prediction of lenvatinib response.

cancer biology↗

bioRxiv2026

TRAPPC8 Is an Endogenous Brake on UFMylation That Suppresses Tauopathy

UFMylation, a ubiquitin-like protein modification, drives tau spread through the brain, but what keeps this process in check has remained unclear. We show that TRAPPC8 acts as a natural brake on UFMylation, binding directly to the E1 enzyme UBA5 to dampen pathway activity. In Alzheimer's disease brain tissue, TRAPPC8 is reduced while UFMylation is elevated, suggesting this brake fails as disease progresses. Sustaining UFMylation in human iPSC-derived neurons increased tau aggregation and spread while disrupting lysosomal function and lipid balance. Restoring TRAPPC8-UBA5 binding reversed these defects through the lysosomal protein CLN8, which restored lysosomal function and reduced tau pathology. Notably, expressing just the UBA5-binding region of TRAPPC8 was enough to suppress tau pathology in vivo, marking it as a promising therapeutic target.

neuroscience↗

bioRxiv2026

Spatial vascular/BTB remodeling and malignant-state plasticity in glioblastoma

Background: Glioblastoma (GBM) contains spatially heterogeneous malignant and vascular states, but blood-tumor barrier (BTB) remodeling is often described as a binary functional phenotype. We asked whether anatomically distinct GBM compartments contain separable vascular programs that coexist with malignant-state plasticity. Methods: We performed donor-aware cross-sectional analyses of 38 histopathology-annotated spatial transcriptomic sections from 6 donors and a separately analyzed endothelial single-nucleus layer from the same GBM-Space atlas. Complementary external datasets tested patient-paired regional remodeling, anatomical replication, cross-technology source localization, and malignant-state architecture. Results: THSD1-FLT4 Recognition increased from leading edge to infiltrative tumor (median adjusted effect +0.02875; 4/4 donors positive). Priming increased across this boundary (+0.14814; 3/4) but decreased from infiltrative to cellular tumor (-0.16409; 0/4), whereas Gate remodeling increased from infiltrative to cellular tumor (+0.21296; 4/4). Remodeled endothelium showed higher PLVAP detection (+0.26409; 12/12 donors) and PLVAP pseudobulk expression (+1.61784 log1pCPM; 11/12), with lower MFSD2A pseudobulk expression (-0.71448; 10/12 negative). External cohorts supported regional vascular/BTB remodeling, while GSE131928 supported broad malignant-state architecture and an exploratory within-tumor pseudotemporal continuum. Conclusions: GBM contains spatially partitioned vascular/BTB-associated programs alongside malignant-state plasticity. Recognition-Priming-Gate is a cross-sectional discovery framework, not a validated temporal cascade, and the data do not establish BTB permeability, causal tumor-vascular signaling, or therapeutic-delivery benefit.

cancer biology↗

bioRxiv2026

Inorganic Nitrogen Availability Drives Metabolic Specialization and Adaptive Strategies in Vibrio harveyi and Vibrio parahaemolyticus

Nitrogen availability is a key factor shaping microbial metabolism, ecological adaptation, and nitrogen cycling in aquatic environments. Members of the genus Vibrio are ubiquitous heterotrophic bacteria in marine and aquaculture ecosystems, yet their responses to different inorganic nitrogen sources remain poorly understood. Here, we systematically compared the growth characteristics, nitrogen transformation capacity, and molecular responses of Vibrio harveyi and Vibrio parahaemolyticus under ammonium (NH4+), nitrate (NO3-), and nitrite (NO2-) conditions using physiological assays, comparative genomic analysis, and transcriptomic profiling. V. harveyi exhibited broader nitrogen utilization capacity and was able to grow under all three nitrogen conditions, whereas V. parahaemolyticus showed a strong preference for NH4+ and limited growth under NO3- and NO2- conditions. Moreover, V. harveyi displayed rapid population expansion accompanied by reduced long-term viability, while V. parahaemolyticus maintained greater population stability. Both species showed NO3- accumulation during growth despite lacking canonical nitrification genes under NH4+ condition, suggesting the potential involvement of non-canonical heterotrophic nitrification processes. Transcriptomic analysis revealed nitrogen source-dependent metabolic specialization in V. harveyi. NH4+ availability promoted motility-associated responses and metabolic overflow, whereas NO3- induced iron acquisition-related pathways and NO2- activated assimilatory nitrite reduction coupled with oxidative stress adaptation. These findings demonstrate that inorganic nitrogen availability drives divergent metabolic and adaptive strategies in Vibrio, providing new insights into their nitrogen metabolic potential and ecological roles in aquatic environments.

microbiology↗

bioRxiv2026

Cytoplasmic DNA Sensing Links LINE-1 Expression to Neuronal Senescence in Alzheimer's Disease

Cellular senescence contributes to neurodegeneration in Alzheimers disease (AD), yet brain-penetrant senotherapeutic strategies remain limited. Here, we identify long interspersed nuclear element 1 (LINE-1) retrotransposons as key regulators of neuronal senescence and the senescence-associated-secretory-phenotype (SASP) in AD. Using transdifferentiated induced neurons (iNs) that preserve donor-specific aging-associated molecular signatures, we show that pharmacological inhibition of LINE-1 with nucleoside reverse transcriptase inhibitors (nRTIs) or antisense oligonucleotides reduces p16 expression, suppresses SASP and interferon-stimulated gene programs, and attenuates paracrine induction of reactive astrogliosis. Spatial transcriptomic analysis of human AD brain tissue further supports that senescent neurons with high LINE-1 expression are localized to inflammatory niches in the brain. Although bulk analysis finds no significant differences in LINE-1 expression between AD and control neurons, long-read single-cell RNA sequencing of iNs identifies a subset of neurons with elevated LINE-1 activity which display transcriptional signatures of neurodegeneration, immune activation, and senescence are enriched in AD relative to controls. RNA velocity analysis indicates that LINE-1 activation precedes the induction of canonical senescence markers, supporting a causal rather than consequential role. Mechanistically, LINE-1-derived cytoplasmic DNA activates the cGAS-STING innate immune pathway in post-mitotic neurons, and inhibition of cGAS phenocopies the effects of LINE-1 suppression. Together, these findings establish a LINE-1/cGAS-STING axis as a driver of neuronal senescence in AD and highlight LINE-1 inhibition as a tractable senomorphic strategy for neurodegenerative disease.

neuroscience↗

bioRxiv2026

Humanized tauopathy chimeras uncover microglial and lncRNA strategies for neuroprotection

Human genetics implicates innate immunity as a key modifier of tau toxicity, yet human-specific neuroimmune mechanisms remain difficult to test in vivo. Here, we developed HuMiNAX, the first humanized iPSC-based neuroimmune xenograft model of tau-associated neurodegeneration, enabling human microglia to interact with human neurons and astrocytes in the adult mouse brain. In HuMiNAX, tau seeding induced aggregation only in mutation-carrying human neural grafts, causing neuron loss and inflammatory activation of human microglia. Progranulin-overexpressing human microglia dampened tau-associated inflammation, preserved neurons, and restored neuronal gene-expression and RNA-splicing programs, supporting microglial control of neuronal resilience. CRISPRi knockdown of the human-specific lncRNA HNRNPK-AS1 also protected neurons in HuMiNAX. These findings establish HuMiNAX as a human neuroimmune model of tauopathy and identify microglial and RNA-mediated strategies of neuronal resilience.

neuroscience↗

bioRxiv2026

Microglial sTREM2 limits dyskinesia and acts on TrkB to support circuit plasticity

Microglia continuously survey the brain and shape neuronal activity, but their contribution to experience-dependent synaptic plasticity is unclear. Levodopa-induced dyskinesia (LID) is a disabling complication of late-stage Parkinsons disease (PD) that is linked to maladaptive striatal remodeling and is often assumed to reflect detrimental neuroinflammation. Here we identify a dyskinesia-associated microglial gene program in the striatum of PD patients and show that microglia instead act as a protective brake on LID. In a mouse model, microglial depletion exacerbated dyskinesia, whereas microglial repopulation mitigated it. Delivery of AAV expressing soluble TREM2 (sTREM2) similarly reduced LID without impairing the therapeutic benefit of levodopa. Single-nucleus transcriptomics revealed that microglial loss drives extensive remodeling of both direct and indirect spiny projection neurons (SPNs), while repopulation or sTREM2 reverses a large fraction of LID-associated transcriptional changes. Mechanistically, sTREM2 directly engages TrkB and potentiates BDNF-dependent TrkB-ERK signaling, consistent with positive allosteric modulation. Functionally, sTREM2 enhances BDNF-TrkB-dependent hippocampal synaptic plasticity and acutely rebalances striatal dendritic excitability in a compartment- and cell type-specific manner. These findings reveal an unexpected neuroimmune pathway in which microglia restrain maladaptive plasticity via sTREM2-TrkB signaling, with therapeutic implications.

neuroscience↗

bioRxiv2026

A NOVEL MITOCHONDRIAL PEPTIDE ESSENTIAL FOR RESPIRATORY CAPACITY PROMOTES GROWTH, YIELD AND ABIOTIC STRESS TOLERANCE IN PLANTS

Efforts to boost crop productivity have focused on improving photosynthesis. However, plant respiration consumes over 90% of fixed carbon, fueling growth, stress responses, and resource acquisition. Despite its metabolic centrality, respiratory regulation remains underexplored as a yield target. Here, we identify AtMLSP1 (At4g17085), a 57-amino-acid mitochondrial inner membrane peptide in Arabidopsis thaliana. Loss-of-function atmlsp1 mutants show impaired growth, while AtMLSP1 overexpression boosts biomass, seed yield, and high light tolerance. No induction of alternative oxidase protein abundance or activity was observed in atmlsp1 plants, a response normally triggered by respiratory perturbation. Mitochondria isolated from atmlsp1 lines had an approximately 90% reduction in the amount of the intermembrane space protein Cytochrome c and a 30% reduction in all subunits of complex III, while other respiratory complexes remain unaffected. As expected, loss-of-function plants atmlsp1 reveal a significant decrease in total respiratory capacity and membrane potential, but mitochondrial integrity, and abundance of complex I, II and complex IV were unchanged. Overexpression of the orthologues of this gene in Oryza sativa (rice) and Glycine max (soybean) results in a significant increases in yield (seed number and size) under field conditions across different locations.

plant biology↗

bioRxiv2026

Interactome mapping in human excitatory neurons reveals novel risk genes and pathways in Alzheimer's disease

Alzheimers disease (AD) is an irreversible neurodegenerative disease defined by its molecular hallmarks - amyloid beta peptide plaques and neurofibrillary Tau tangles. Despite significant progress that has been made in uncovering a large number of genetic risk factors through extensive genomic sequencing and genetic studies, the molecular mechanisms driving AD-associated pathology and cognitive decline remain poorly understood. Therefore, alongside the identification of more risk genes, it is also paramount to study how these genes function and influence each other within the cellular pathways and overall molecular networks in AD-relevant brain cell types. However, current human protein-protein interactome datasets were all generated in either yeast or generic human cell lines. Consequently, many important neuronal interactions, especially neuron-specific ones, have yet been discovered. To address this critical gap, we developed a highly scalable, high-quality interactome mapping pipeline in human excitatory neurons derived from induced pluripotent stem cells (iPSC), and generated a comprehensive, neuron-specific interactome map, named ADNeuronNet, for key AD risk genes. ADNeuronNet consists of 1,767 high-confidence interactions among 1,189 proteins and is the only dataset enriched with neuron-specific genes when compared to known protein interactions, including previous large-scale interactome maps, for the same baits in the literature. Within ADNeuronNet, we identified 1,375 novel interactions, many of which are likely neuron specific. For example, we identified a neuron-specific interactor, RIN2, for major AD risk factor BIN1 and confirmed RIN2s function in recruiting BIN1 to RAB5 positive early endosomes, a process that has been well-associated with AD etiology. Additionally, we performed quantitative interaction perturbation analyses on AD risk genes with AD-associated mutations or isoforms and identified significant changes in 99 protein interactions among 11 different protein variants. Finally, we found that subunits from the anaphase-promoting complex/cyclosome (APC/C), another novel BIN1 interactors identified by ADNeuronNet, mediated modulation of Tau-aggregation in neurons via regulation of APOE expression, uncovering a previously unrecognized BIN1-APC/C-APOE regulatory axis in AD pathobiology. In summary, these findings illustrate how our neuron-specific ADNeuronNet can be leveraged to uncover new risk gene candidates and cellular pathways that help advance our understanding of molecular mechanisms underlying AD etiology.

systems biology↗

bioRxiv2026

cGAS inhibition delays TDP-43-driven ALS Pathogenesis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by motor neuron loss and cytoplasmic mislocalization of TAR DNA-binding protein 43 (TDP-43), a key regulator of RNA splicing. However, the upstream modulators of this process remain poorly defined. Here we identify cyclic GMP-AMP synthase (cGAS) as a central mediator of TDP-43 pathology and associated mis-splicing. cGAS expression was elevated in ALS patient brains and enriched across activated microglia. In human iPSC-derived microglia-motor neuron co-cultures, neuronal TDP-43 pathology triggered microglial cGAS activation, whereas pharmacological inhibition with a potent human cGAS inhibitor reduced phosphorylated TDP-43, restored lysosomal and phagocytic programs, normalized microglial reactivity, and reversed TDP-43-associated RNA splicing defects. In vivo, cGAS inhibition in TDP-43 Q331K mice reversed widespread RNA splicing abnormalities across neurons and oligodendrocyte lineage cells, attenuated neurodegenerative pathology, and preserved motor function. Together, these findings identify cGAS as a druggable upstream regulator linking innate immune signaling to TDP-43-dependent RNA mis-splicing and neurodegeneration, and establish cGAS inhibition as a promising therapeutic strategy for ALS.

neuroscience↗

bioRxiv2026

cGAS-mediated IFN-I signaling contributes to disease progression in drug-refractory epilepsy

Epilepsy is a prevalent neurological disease with a third of patients becoming non-responsive to antiepileptic drugs and developing drug-refractory epilepsy (DRE). Here we report that DRE disease progression is contributed by overactive cyclic GMP-AMP synthase (cGAS), a double-stranded DNA sensor that induces type I interferon (IFN-I) signaling. In human DRE microglia, we observe a robust IFN-I signature and the activation of upstream cGAS-STING signaling. Further, in mouse models of Dravet syndrome, a genetic form of DRE, we observe the activation of the cGAS pathway. We show that microglial cGAS can be activated by DNA released from hyperexcitable neurons. Genetic reduction and pharmacological inhibition of cGAS reduces epileptic phenotypes, glial inflammatory signatures, and neuronal transcriptomic changes, underscoring the therapeutic potential of targeting cGAS for DRE treatment.

neuroscience↗

bioRxiv2026

Soluble DLK1 secreted by telomere-shortening-induced senescent microglia impairs oligodendrocyte functions and alters neuronal activity

Aging is the major risk factor for neurodegenerative disease, yet the mechanisms linking physiological aging to brain dysfunction remain unclear. Because telomere erosion is a hallmark of aging, we examined its impact on glial and neuronal physiology. Telomere shortened mice showed lipofuscinosis, hypomyelination, microglial atrophy, and cognitive deficits. Single nuclei RNA-seq revealed accelerated glial aging, elevated microglial senescence pathways, and impaired oligodendrocyte functions. Inducing senescence in human iPSC derived microglia with shortened telomeres identified soluble DLK1 as a novel senescence associated ligand. sDLK1 was increased in the cerebrospinal fluid of telomere shortened and naturally aged mice, and this increase was eliminated by microglial depletion. AAV delivery of sDLK1 in vivo caused hypomyelination and blocked oligodendrocyte lineage progression, demonstrating the detrimental nature of excessive sDLK1. In human iPSC systems, sDLK1 impaired oligodendrocyte maturation and altered calcium signaling in excitatory neurons. These findings identify microglial senescence as a core consequence of telomere shortening and reveal sDLK1 as a microglia-derived senescence ligand that drives oligodendrocyte and neuronal dysfunction in aging.

neuroscience↗

bioRxiv2026

Transplantation of Human IPSC-derived Microglia Ameliorates Neuropathology and Circuit Dysfunction in Progranulin-Deficient Mice

Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading genetic cause of familial FTD, disrupts lysosomal function, lipid metabolism, autophagy, and neuroimmune signaling across multiple cell types. Increasing evidence indicates that microglia are particularly sensitive to progranulin loss, exhibiting elevated complement activation that contributes to TDP-43 proteinopathy and neuronal dysfunction. Here, we investigate the biological role of restoring progranulin exclusively within microglia by transplanting human induced pluripotent stem cell-derived microglia (iMG) into progranulin (Grn)-deficient mice. We find that wild-type, but not Grn-deficient, human iMG restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss. Because microglia are the only source of progranulin in this system, these findings demonstrate that microglial progranulin is sufficient to restore key aspects of cellular, circuit, and behavioral homeostasis in a progranulin-deficient FTD model. More broadly, this work highlights a central, microglia-intrinsic role for progranulin in maintaining brain function and provides a framework for dissecting microglia-specific mechanisms across FTD and related neurodegenerative disorders. One Sentence SummaryOur study demonstrates that xenotransplantation of wild-type human iPSC-derived microglia into progranulin-deficient mice mitigates core neuropathological, network-level, and behavioral features of Frontotemporal Dementia.

neuroscience↗

bioRxiv2025

Inducible CreERT2 mouse lines for characterization of retinal bipolar cell subtypes

Bipolar cells relay visual signals from photoreceptor cells to ganglion cells in the retina. Fifteen bipolar cell subtypes have been identified in the mouse retina. These subtypes are classified as ON and OFF bipolar cells based on their response to light stimulus or rod and cone bipolar cells based on their connection to photoreceptor cells. However, the unique structural and functional role of these subtypes in the processing of visual information is not fully known due to the inadequate tools and models available for their characterization. In this study, to trace the lineage and characterize Vsx1, Lhx3, and Lhx4 - expressing bipolar cell subtypes in developing and adult mouse retina, we developed inducible Cre lines under the promoter of Vsx1, Lhx3, and Lhx4 and crossed them with ChR2EYFP reporter mice. Lineages of cells expressing Vsx1, Lhx3, and Lhx4 after Cre induction in the adult and postnatal mouse retina were then characterized. ChR2EYFP expression driven by Vsx1-CreERT2 was detected in type 2, 6, and 7 bipolar cells, Lhx3-CreERT2 in type 1b, 2, and 6 bipolar cells, and Lhx4-CreERT2 in type 2, 3, 4, and 5 bipolar cells as well as cone photoreceptor cells in the adult mouse retina. These bipolar cell subtype-specific inducible Cre mouse lines serve as efficient tools for elucidation of the mechanisms that control bipolar cell subtype development and function in the retina. Significance StatementBipolar cells are central connectors of the outer and inner retina and initiate processing of complex visual information. Bipolar cells differentiate into more than fifteen subtypes during development, and their structural diversity has been well studied. However, the unique contribution of these subtypes to the processing of visual information is poorly understood due to inadequate tools. In this study, we develop and characterize three inducible Cre mouse models for in vivo and temporally defined genetic manipulation in bipolar cell subtypes in the developing and adult mouse retina. These models serve as tools to elucidate the mechanisms that regulate the development and function of bipolar cell subtypes in the mouse retina.

neuroscience↗

bioRxiv2025

STING_IFN_CH25H lipid axis links innate immune activation to tau pathology

Genetic risk for Alzheimers disease is strongly enriched in pathways governing microglial activation and cholesterol metabolism, yet how these processes converge to drive neurodegeneration remains unclear. Here, we identify the oxysterol 25-hydroxycholesterol (25- HC) as a pathogenic lipid downstream of the cGAS-STING-IFN pathway. In models of tau pathology, interferon signaling induces Cholesterol 25-hydroxylase (CH25H) expression in microglia. Ch25h deletion in female P301S mice suppressed tau aggregation, preserved synapses, prevented brain atrophy, and rescued memory. Mechanistically, loss of CH25H disrupted STING trafficking, attenuated IFN activation, dampened self-perpetuating microglial inflammation. Strikingly, 25-HC directly accelerated tau propagation in human iPSC derived neurons. It also disrupted lysosomal and mitochondrial lipid composition, driving cholesteryl ester accumulation and promoting apoptosis under tau-induced stress. These findings define a STING-IFN-CH25H lipid axis that bridges innate immune activation to tau pathology and toxicity, offering a tractable therapeutic pathway for inflammation-driven neurodegenerative conditions.

neuroscience↗