Biology subjects

Qiu, S.

Publications and source records attributed to Qiu, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Erythropoietin Mediates Glycerophospholipid Remodeling During Human Early Erythropoiesis

The unique biconcave morphology and deformability of mature red blood cells (RBCs) require a specific membrane lipid composition. Disruption of this special lipid profile is seen in multiple types of anemia and bone marrow (BM) failure diseases, yet molecular mechanisms regulating lipid metabolism during normal erythroid differentiation remain poorly defined. Here, we identify a previously undescribed role for erythropoietin (Epo) in contributing to the appropriate lipid composition of differentiating human erythroid cells. Using single-cell transcriptomic profiling of ex vivo cultures of human BM-derived hematopoietic stem and progenitor cells cultured with or without Epo, we delineated transcriptional dynamics across differentiation stages, identifying the Epo-dependent transition of burst-forming unit erythroid (BFU-E) to colony-forming unit erythroid (CFU-E) progenitors. Comparative analysis revealed the activation of canonical erythroid programs involving heme biosynthesis, globin expression, and iron regulation, and additionally, uncovered a transient upregulation of lipid metabolic pathways during the BFU-E to CFU-E transition. Complementary untargeted lipidomics demonstrated Epo-dependent alterations in specific glycerophospholipid (GPL) species, consistent with differential expression of GPL biosynthesis genes in the single cell dataset. Intracellular flow cytometry further confirmed the requirement of Epo for maintaining enzymes critical for phosphatidylcholine and phosphatidylethanolamine synthesis in erythroid cells. Together, these multiomic findings reveal a new role for Epo in modulating lipid metabolism during early erythropoiesis and provide mechanistic insight into how membrane lipid composition is dynamically regulated to support normal red cell development.

cell biology↗

bioRxiv2026

Multimodal Behavior Scoring quantifies depression-like severity across chronic stress models and identifies stress-resilient mice

IntroductionRodent chronic-stress models are central to preclinical depression research, yet behavioral phenotypes are often assessed assay-by-assay, which can reduce cross-cohort comparability and mask heterogeneity across symptom domains (e.g., anhedonia, anxiety-like behavior, and behavioral despair). An integrative behavioral index may provide a more robust and interpretable measure of overall stress-induced severity and facilitate stratification of susceptible versus resilient individuals. MethodsWe developed the Multimodal Behavior Scoring (MBS) algorithm to integrate outcomes from standard assays--sucrose preference test (SPT), open field test (OFT), and forced swim test (FST)--into a unified severity score. MBS was evaluated in two independent paradigms, chronic unpredictable mild stress (CUMS) and chronic social defeat stress (CSDS), quantifying group discrimination, reproducibility (intraclass correlation coefficient, ICC), and phenotypic stratification. ResultsMBS robustly separated stressed from control mice (CUMS: +39.8%, p<0.0001; CSDS: +121.8%, p<0.0001) and showed high cross-cohort reproducibility (ICC>0.88). MBS further identified stress-resilient subpopulations and uncovered paradigm-specific behavioral signatures, with despair-dominant patterns in CUMS (FST-MBS, r=0.61) and anxiety-centric patterns in CSDS (OFT-MBS, r=-0.74). Excluding TST did not reduce discrimination performance. ConclusionMBS provides an integrative framework for quantifying depression-like behavioral severity and heterogeneity, enabling streamlined protocols and improving the translational utility of preclinical cohorts for biomarker discovery and antidepressant screening.

animal behavior and cognition↗

bioRxiv2026

Circuit-Specific Resting-State fMRI Signatures for Stratifying First-Episode Major Depressive Disorder and Predicting Recurrence Risk

BackgroundDepression is biologically heterogeneous, and first-episode depression (FED) carries a high risk of recurrence that is poorly captured by symptom-based assessment. Early identification of patients likely to relapse, as well as reliable identification of those unlikely to relapse, is needed to support personalized intervention and efficient allocation of care. MethodsWe developed a neurocomputational framework to infer recurrence risk from resting-state fMRI functional connectivity. The framework combines a Convolutional Filtering Autoencoder (CFAE) with a k-medoids clustering algorithm (FED-kMC) to derive neurofunctional FED subtypes, followed by a Manifold Sheaves-based Ensemble Support Vector Machine (MST-LVSVM) to estimate individual-level recurrence risk and define an interpretable decision boundary. Circuit-level analyses were then used to localize connectivity pathways associated with high relapse risk. ResultsThe framework identified two neurofunctionally distinct FED subtypes with divergent recurrence trajectories and achieved an external validation accuracy of 82.61% for recurrence risk prediction. Circuit analyses highlighted dysfunction within the Medial Superior Frontal Gyrus-Hippocampus and Angular Gyrus-Precuneus pathways as neural correlates of high relapse risk, together with a decision boundary enabling early-stage risk stratification. ConclusionsIntegrating connectome-derived, circuit-level information with subtype-aware machine learning may support proactive identification of FED patients at elevated recurrence risk and facilitate targeted early interventions, bridging connectome-level analysis and clinical decision-making.

neuroscience↗

bioRxiv2026

NF1 Loss Remodels Tumor Niches for Immune Evasion

Genetic and transcriptional alterations in cancer cells shape their interactions with immune and stromal compartments, influencing tumor progression, immune evasion, and response to immune checkpoint inhibitors (ICI). Yet, how these interactions are organized within tumor architecture and linked to clinical outcomes remains unclear. Neurofibromin 1 (NF1) is a tumor suppressor gene that is frequently inactivated across multiple cancer types. NF1 loss-of-function mutations occur in up to 27% of melanoma cases and are associated with poor clinical outcomes. Here, we used spatial multi-omics analysis to uncover 12 meta-niches, each comprising distinctive cell types with distinct characteristics, in human melanoma tissues. We found that niches containing immunosuppressive cancer-associated fibroblasts (CAFs) and macrophages were significantly enriched in NF1 mutant melanoma (NF1Mut) tissues. In contrast, niches containing cytotoxic CD8 T cells were significantly diminished. NF1 loss correlates with increased epidermal growth factor signaling (EGFR) signaling and reduced antigen presentation in tissues with limited CD8 T cell infiltration in both human and mouse melanoma. We demonstrate that EGFR inhibition restores antigen presentation and activates immune responses in a syngeneic Nf1 knockdown model resistant to ICIs. These data, therefore, define functionally distinctive niches enriched in NF1Mut melanoma that likely contribute to their aggressive nature and nominate EGFR signaling as a specific target to reinvigorate ICI responses. We therefore link an understudied genetic driver to specific immune architectures and ultimately therapy resistance and suggest a therapeutic strategy expected to improve treatment outcomes in NF1Mut melanoma patients.

cancer biology↗

bioRxiv2025

Transcriptional Profiling of D1-MSNs Reveals SIRT1-Dependent and -Independent Responses to Chronic Social Defeat Stress

SIRT1 is a critical regulator of neuronal functions and has been implicated in various neurological disorders, including depression. In a previous study, we demonstrated the pro-depressive roles of SIRT1 in the nucleus accumbens (NAc) using the chronic social defeat stress (CSDS) model, a well-validated preclinical mouse model of depression. We found that SIRT1 modulates synaptic functions and exhibits pro-susceptible effects specifically in D1-medium spiny neurons in the NAc. In this study, we extended our investigation of SIRT1 functions by employing cell-type-specific transcriptomics to compare control and susceptible groups under CSDS. Our results revealed that in wild-type mice with functional SIRT1, cellular metabolism is crucial for inducing susceptibility to depression. Conversely, in the absence of functional SIRT1 expression, circadian clock-controlled transcriptional regulation becomes a key factor. These findings suggest that SIRT1 differentially modulates key pathophysiological mechanisms of depression via its deacetylase functions, highlighting its role in both metabolic and circadian regulation in the brain. This research provides new insights into the molecular underpinnings of depression and identifies potential targets for therapeutic intervention.

neuroscience↗

bioRxiv2025

Proteome constrained metabolic modeling of Sus scrofa muscle stem cells for cultured meat production

Cultured meat has recently emerged as a sustainable alternative to the traditional livestock farming and gained attention as a promising future protein source. Herein, the Sus scrofa muscle stem cell is a commonly used cell source in the cell proliferation step of cultured meat production. However, a major bottleneck of large-scale cultivation is the inhibition by secreted and accumulated lactate and ammonium in the process of S. scrofa cell proliferation. To simulate the growth and metabolism of S. scrofa muscle stem cells under different lactate and ammonium concentrations, this study constructed the first proteome constrained metabolic model for the core metabolism of S. scrofa muscle stem cells, pcPigGEM2025. The relationship of lactate and ammonium levels with cellular metabolism was derived from growth and metabolomics data of two culture conditions with low and high initial ammonium concentrations, and then incorporated into metabolic flux simulation. Metabolic flux simulations for experimental conditions, along with perturbation simulations considering stressed non-growth associated maintenance and oxygen supply, demonstrated that pcPigGEM2025 could effectively characterize the response of the S. scrofa muscle stem cells growth and metabolism to varying environmental conditions, shedding light on model-aided control and optimization of the cultured meat production process. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=98 SRC="FIGDIR/small/679571v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@a4526aorg.highwire.dtl.DTLVardef@1ee2d1org.highwire.dtl.DTLVardef@1bd4700org.highwire.dtl.DTLVardef@18079e6_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIThe first proteome constrained metabolic model was built for S. scrofa myoblasts. C_LIO_LIThis model effectively simulated myoblast metabolism under lactate and NH4+ stress. C_LIO_LIPerturbation simulations showed that this model could also account for other stress. C_LIO_LIThis model enables in-silico control and optimization of cultured meat production. C_LI

bioengineering↗

bioRxiv2025

Analysis of Nutritional Components in Brown Sugar and Its Effects on Anti-fatigue, Alleviation of Qi Deficiency and Blood Stasis, and Antioxidant Effects

Brown sugar (BS), Red granulated sugar (RGS) and White sugar(WS) are three key sweeteners and food additives in China. Notably, BS possesses significant nutritional value and has been widely used in Chinese medicine for its supportive therapeutic properties.This study evaluated the anti-fatigue, the amelioration of qi deficiency and blood stasis, as well as the antioxidant activities of these sugars using a zebrafish model. BS and RGS demonstrated significantly greater efficacy than WS in terms of both anti-fatigue effects and amelioration of qi Deficiency and blood stasis in the zebrafish model. Antioxidant assays revealed that BS, RGS, and WS (500 g/mL) significantly enhanced superoxide dismutase (SOD) activity in zebrafish embryos compared with the control group. Furthermore, the mineral composition of sugar were determined. Nine mineral elements--potassium (K), calcium (Ca), sodium (Na), magnesium (Mg), iron (Fe), zinc (Zn), copper (Cu), phosphorus (P), and selenium (Se)--were analyzed. BS exhibited markedly higher concentrations of P, Ca, Fe, and Mg than RGS and WS, while selenium (detected at 50 mg/kg) was exclusively detected in BS. Intriguingly, RGS contained four-fold higher potassium levels than BS. Total polyphenol content, quantified by Folin-Ciocalteu assay, was 4.35 g/kg in BS and 1.53 g/kg in RGS, with no detectable polyphenols in WS.

biochemistry↗

bioRxiv2025

Neurogranin Unlocks the L-type Ca2+ Channel and Directs Calmodulin Delivery

Neurogranin (Ng) is enriched in the postsynaptic density, with mounting evidence of its importance to neural pathophysiology. Ng has long been recognized as a dedicated calmodulin (CaM)- binding/buffering protein. This study demonstrates that Ng, through its CaM-binding IQ domain, directly binds the distal C-terminus (DCT) of the L-type Ca2+ (CaV1) channel, as a de novo mechanism regulating excitation-transcription coupling. The Ng/DCT interaction attenuates autonomous C- terminus-mediated inhibition and promotes specific CaM delivery to CaV1, cooperatively enhancing channel gating (activation and inactivation), Ca2+ influx and downstream neuronal signaling. Phosphorylation of Ng leads to the dissociation of the CaM C-lobe, while transiently forming the linkage with the CaM N-lobe. In contrast to neurodegenerative disease-related Ng mutants, WT Ng, within the above transient complex, enables the "targeted CaM transfer" to the proximal C-terminus of CaV1. Collective evidence from electrophysiology, binding assays, structural modeling and Ca2+ imaging supports a paradigm of dynamic intra- and inter-molecular interactions/facilitations underlying Ng and CaV1, both of which are representative CaM-binding proteins. This work proposes a mechanistic scheme potentially applicable to a broad scope of CaM-related physiology.

biophysics↗

bioRxiv2025

Population-specific brain charts reveal Chinese-Western differences in neurodevelopmental trajectories

Human brain charts provide unprecedented opportunities for decoding neurodevelopmental milestones and establishing clinical benchmarks for precision brain medicine 1-7. However, current lifespan brain charts are primarily derived from European and North American cohorts, with Asian populations severely underrepresented. Here, we present the first population-specific brain charts for China, developed through the Chinese Lifespan Brain Mapping Consortium (Phase I) using neuroimaging data from 43,037 participants (aged 0-100 years) across 384 sites nationwide. We establish the lifespan normative trajectories for 296 structural brain phenotypes, encompassing global, subcortical, and cortical measures. Cross-population comparisons with Western brain charts (based on data from 56,339 participants aged 0-100 years) reveal distinct neurodevelopmental patterns in the Chinese population, including prolonged cortical and subcortical maturation, accelerated cerebellar growth, and earlier development of sensorimotor regions relative to paralimbic regions. Crucially, these Chinese-specific charts outperform Western-derived models in predicting healthy brain phenotypes and detecting pathological deviations in Chinese clinical cohorts. These findings highlight the urgent need for diverse, population-representative brain charts to advance equitable precision neuroscience and improve clinical validity across populations.

neuroscience↗

bioRxiv2025

Garcinone C suppressed the proliferation of gastric cancer cells through regulating Hedgehog signaling

Garcinone C, a xanthone derived from Garcinia mangostana L, possesses antioxidant and anti-cancer effects. However, its role in gastric cancer remains unexplored. This study aimed to investigate the effects of garcinone C on gastric cancer cell proliferation and its underlying mechanism. We found that garcinone C suppressed gastric cancer cell growth by inducing G0/G1 arrest and apoptosis in a dose-dependent manner. Furthermore, garcinone C downregulated G0/G1 phase markers Cyclin D1 and p21, as well as apoptosis markers Bax, Bcl-2, cleaved-PARP, and c-caspase 3. Following the previous evidence demonstrated that aberrant Hedgehog (Hh) signaling is implicated in gastric cancer development, we confirmed that inhibiting Gli1/2 reduced the growth of AGS and MKN74 cells. Furthermore, garcinone C exerted similar effects to Gant61, inhibiting Hh signaling by reducing Gli1/2 levels and blocking their nuclear translocation. These findings suggest that garcinone C inhibits gastric cancer proliferation via the Hh signaling, indicating its potential as a therapeutic agent for treating gastric cancer.

cancer biology↗

bioRxiv2025

Co-phagocytosis of VEGFA with HER2-overexpressing cancer cells induced by HER2-VEGFA BsAb improves antitumor responses

We conceived of a new anti-tumor mechanism of action by which a soluble target in tumor microenvironment, such as a tumor-driving growth factor, can be phagocytized along with cancer cells via antibody-dependent cellular phagocytosis (ADCP) using an antibody bispecific for the soluble target and a solid target overexpressed on cancer cell surface. In this study, we explored the conception through engineering a pair of bispecific antibodies (BsAbs) co-targeting human epidermal growth factor receptor-2 (HER2) and human or mouse vascular endothelial growth factor A (VEGFA). We showed that the HER2-VEGFA BsAbs but not the parental antibodies alone or in combination induced co-phagocytosis of VEGFA and HER2-overexpressing cancer cells by tumor-associated macrophages via ADCP. In both immunocompromised and immunocompetent mice with aggressive tumors, the BsAbs demonstrated a greater anti-metastasis activity and had a greater survival benefit than the parental antibodies, alone or in combination, in a manner dependent on Fc{gamma} receptors on the macrophages. Our results provide the proof-of-concept to induce VEGFA co-phagocytosis using HER2-VEGFA BsAbs to achieve enhanced antitumor activities by leveraging overexpressed HER2 on cancer cell surface. Our findings warrant clinical testing of the humanized BsAb to treat metastasis and recurrence of HER2-overexpressing solid tumors that respond to anti-VEGFA therapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/648615v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@102cb83org.highwire.dtl.DTLVardef@7f2dfborg.highwire.dtl.DTLVardef@1a3dad1org.highwire.dtl.DTLVardef@72ff5e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

A versatile miniature two-photon microscope enabling multicolor deep-brain imaging

Here we present the FHIRM-TPM 3.0, a 2.6 g miniature two-photon microscope capable of multicolor deep-brain imaging in freely behaving mice. The system was integrated with a broadband anti-resonant hollow-core fiber featuring low transmission loss, minimal dispersion from 700-1060 nm, and high tolerance of laser power. By correcting chromatic and spherical aberrations and optimizing the fluorescence collection aperture, we achieved cortical neuronal imaging at depths exceeding 820 m and, using a GRIN lens, hippocampal Ca2+ imaging at single dendritic spine resolution. Moreover, we engineered three interchangeable parfocal objectives, allowing for a tenfold scalable field-of-view up to 1x0.8 mm{superscript 2}, with lateral resolutions ranging from 0.68 to 1.46 m. By multicolor imaging at excitation wavelengths of 780 nm, 920 nm and 1030 nm, we investigated mitochondrial and cytosolic Ca2+ activities relative to the deposition of amyloid plaques in the cortex of awake APP/PS1 transgenic mice. Thus, the FHIRM-TPM 3.0 provides a versatile imaging system suitable for diverse brain imaging scenarios.

neuroscience↗

bioRxiv2025

Ustilaginoidea virens suppresses floral immunity through promoting GA biosynthesis by the effector SCRE9

Rice false smut caused by Ustilaginoidea virens has become one of the most important rice diseases. U. virens specifically infects rice florets through stamen filaments. However, it is mysterious how U. virens inhibits floral immunity for successful colonization. Here, we show that a small cysteine-rich effector SCRE9 is a key virulence factor in U. virens. Expression of SCRE9 in rice not only suppresses immune responses and false smut resistance, but also significantly increases expression of expansin and gibberellin (GA) biosynthetic genes and GA content in young rice panicles. We further demonstrate that OsSIP1 (SCRE9-interacting protein 1) in rice is targeted by SCRE9 and interacts with the OsMADS63 and OsMADS68 transcription factors that transcriptionally regulate the GA synthesis gene GA3ox1. Interestingly, the chloroplast-localized OsSIP1 recruits OsMADS63/68 into the chloroplast. SCRE9 causes OsSIP1 to be translocated into the nucleus, thereby releasing OsMADS63/68 from the chloroplast into the nucleus to promote GA3ox1 transcription. Therefore, SCRE9 promotes GA biosynthesis and expression of expansins in rice florets, thus loosening cell walls and overcoming the physical barrier during U. virens infection. The finding uncovers an unidentified floret infection strategy that offsets the deficiency in cell wall degrading ability in the unique floret colonizing fungus.

plant biology↗

bioRxiv2024

Dynamic p21-dependency during quiescence arrest unveiled by a rapid p21 depletion system

Stress- or developmentally-induced signals can trigger G0/G1 cell cycle arrest through the upregulation of p21, a key inhibitor that halts proliferation. While p21 is widely recognized as essential for establishing this arrest, its degradation is generally assumed to be a prerequisite for the exit from arrest and cell cycle re-entry. Using a rapid p21 degradation system that allows for both endogenous p21 tracking and controlled depletion, we uncovered an extended role for p21 during the exit from G0/G1 arrest. Our results showed that removal of the arrest inducing signals did not lead to an immediate decline of p21 during the exit process; instead, p21 levels continued to maintain for a period before its gradual down-regulation. Importantly, premature depletion of p21 during this process weakened the capacity of cell cycle re-entry, particularly in cells with high levels of pre-existent p21. We found that during the release from arrest, cells with high levels of pre-existent p21 but a premature p21 depletion exhibited reduced capacity to restore KRAS/ERK activity, and supplementing KRAS/ERK activity rescued the failure of cell cycle re-entry in these cells. These findings reveal a previously unappreciated function for p21 during the exit from G0/G1 arrest, aside and distinct from its role in initiating the arrest. This new paradigm extends across multiple cell lines and stress-induced arrest contexts, offering a new framework for understanding p21 function in response to anticancer therapies and in development.

cell biology↗

bioRxiv2024

Limitations and Enhancements in Genomic Language Models: Dynamic Selection Approach

1Genomic Language Models (GLMs), which learn from nucleotide sequences, are crucial for understanding biological principles and excel in tasks such as sequence generation and classification. However, state-of-the-art models vary in training methods, architectures, and tokenization techniques, resulting in different strengths and weaknesses. We propose a multi-model fusion approach with a dynamic model selector that effectively integrates three models with distinct architectures. This fusion enhances predictive performance in downstream tasks, outperforming any individual model and achieving complementary advantages. Our comprehensive analysis reveals a strong correlation between model performance and motif prominence in sequences. Nevertheless, overreliance on motifs may limit the understanding of ultra-short core genes and the context of ultra-long sequences. Importantly, based on our in-depth experiments and analyses of the current three leading models, we identify unresolved issues and suggest potential future directions for the development of genomic models. The code, data, and pre-trained model are available at https://github.com/Jacob-S-Qiu/glm_dynamic_selection.

genomics↗

bioRxiv2024

Metabolic Divergence Between Healthy and Conditional Presenilin-1/2 knockout Dementia Model Mice under Chronic Nicotine exposure

Nicotine, a primary bioactive compound in tobacco, influences a wide range of metabolic pathways, with potential implications for neurodegenerative diseases such as Alzheimers disease (AD). This study investigates the metabolic effects of chronic nicotine administration in presenilin-1/2 double knockout (DKO) mice and wild-type (WT) control mice. Eight-month-old DKO and WT mice underwent a three-month oral nicotine administration which did not significantly affect body weight or spontaneous locomotor activity in either DKO or WT mice, as measured by weekly body weight measurement and open field test. The metabolomic analyses were performed using untargeted LC-MS and GC-MS techniques. The results revealed distinct metabolic profiles between DKO and WT mice under nicotine exposure. In DKO mice, nicotine exacerbated deficits in purine and nicotinamide metabolism, further highlighting dysregulation in energy homeostasis. Key findings include reduced adenosine and elevated dopamine levels in DKO serum, alongside increased cotinine concentrations, suggesting altered nicotine metabolism. WT mice showed significant changes in energy and lipid metabolism pathways, though with less pronounced alterations compared to DKO mice. Enrichment analyses identified significant pathway disruptions, particularly in choline metabolism, amino acid metabolism, and central carbon metabolism, with genotype-dependent responses to nicotine. This study highlights the intrinsic metabolic alterations in DKO mice, such as disruptions in purine and nicotinamide metabolism, which contribute to their neurodegenerative pathology and unique responses to nicotine. By revealing the differential metabolic impacts of nicotine on healthy and neurodegenerative states, the findings provide valuable insights into its dual therapeutic and pathological roles. These results may guide future research into the metabolic underpinnings of neurodegeneration and the potential for nicotine as a targeted therapeutic intervention.

neuroscience↗

bioRxiv2024

Deep learning-based prediction of enzyme optimal pH and design of point mutations to improve acid resistance

An accurate deep learning predictor of enzyme optimal pH is essential to quantitatively describe how pH influences the enzyme catalytic activity. CatOpt, developed in this study, outperformed existing predictors of enzyme optimal pH (RMSE=0.833 and R2=0.479), and could provide good interpretability with informative residue attention weights. The classification of acidic and alkaline enzymes and prediction of enzyme optimal pH shifts caused by point mutations showcased the capability of CatOpt as an effective computational tool for identifying enzyme pH preferences. Furthermore, a single point mutation designed with the guidance of CatOpt successfully enhanced the activity of Pyrococcus horikoshii diacetylchitobiose deacetylase at low pH (pH=4.5/5.5) by approximately 7%, suggesting that CatOpt is a promising in-silico enzyme design tool for pH-dependent enzyme activities. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/623957v2_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@ff8b46org.highwire.dtl.DTLVardef@110c721org.highwire.dtl.DTLVardef@817014org.highwire.dtl.DTLVardef@1e55d6a_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Lack of Ameliorative Effect of Chronic Oral Nicotine on Olfactory Dysfunction in Young Adult Presenilin-1/2 Double Knockout Mice of a Dementia Model

Olfactory dysfunction is a prevalent and early feature of neurodegenerative diseases including Alzheimers disease while the features and underlying mechanisms remain inadequately understood. This investigation aimed to elucidate the olfactory function characteristics of presenilin-1/2 double knockout (DKO) mice, an established mouse model of dementia. Through a series of behavioral tests on DKO and wildtype (WT) mice at 2 and 6 months of age, we assessed their abilities in odor detection, discrimination, and olfactory memory. The findings revealed a substantial deficit in odor detection in 2-month-old DKO mice compared to WT mice, with a noteworthy age-related deterioration observed from 2 to 6 months. Although DKO mice exhibited normal odor discrimination and olfactory memory capabilities at 2 months, these functions declined with age, falling significantly lower levels than observed in WT mice by the age of 6 months. Subsequently, 2-month-old DKO and WT mice underwent a 4-month chronic nicotine treatment through drinking water. This intervention failed to ameliorate olfactory dysfunctions in DKO mice and exhibited no significant impact on WT mice, despite a discernible trend of a potential negative effect. In summary, this behavioral study elucidates that Presenilin-1/2 double knockout impairs odor detection in young adult mice and accelerates declines of olfactory discrimination and memory. The chronic administration of nicotine did not effectively mitigate olfactory function deficiencies in young adult DKO mice, and the results also highlight age as an important contributing factor.

animal behavior and cognition↗