Biology subjects

Ding, Y.

Publications and source records attributed to Ding, Y..

At least 91 records · Page 5Linked to original sources

bioRxiv2025

A systematic delineation of 3'UTR regulatory elements and their contextual associations

The 3'UTR encodes regulatory information that shapes transcript abundance and subcellular distribution, yet the underlying sequence rules remain incompletely defined. Using SEERS, we quantified the effects of [~]2 million synthetic 3'UTR inserts in A549 and HCT116 cells on RNA output and nuclear-cytoplasmic partitioning. We identify a broad repertoire of short (2[~]8 nt) elements whose effects largely align along a major coupled axis that links high expression with cytoplasmic enrichment and low expression with nuclear enrichment, and contribute predominantly in an additive manner. A context-aware deep learning model (TALE) captures most of this behavior while revealing that strong context dependence is uncommon and emerges mainly in rare, extreme contexts consistent with higher-order constraints. Applying TALE to ClinVar 3'UTR variants prioritizes a subset of pathogenic SNVs with aberrant predicted effects, frequently explained by creation or disruption of splice-site-like U1 telescripting signals, highlighting a potent route to 3'UTR-driven disease mechanisms.

genomics↗

bioRxiv2025

High-resolution comparative single-cell transcriptomics of doublesex-expressing neurons reveals evolutionary conservation and diversity of sexual circuits in Drosophila

Understanding how the cellular and molecular composition of neural circuits change during evolution is essential for deciphering how behavior evolves. Male sexual behaviors in Drosophila species are remarkably diverse, and the underlying sexual circuits are specified by sex determination genes. Here, we employed single-cell transcriptomics to systematically characterize and compare neuron cell types that express the sex determination gene doublesex in adult males across Drosophila species with divergent sexual behaviors. High-resolution profiling to delineate cellular diversity revealed a largely conserved set of cell types across four species, with minimal evolutionary gain or loss and potentially more prevalent changes in cell type abundance. In-depth comparisons between D. melanogaster and D. yakuba showed that transcriptomic conservation and differentially expressed genes between species are highly cell-type-specific, suggesting that cell types evolve as highly independent units. We identified widespread species differences in gene expression, particularly in the neuromodulatory signaling pathway, while preserving a conserved circuit layout in sexual identity and neurotransmitter properties. We further generated a female dataset in D. melanogaster to define sex differences in cell types and examine species divergence in relation to sex differences. Finally, we reported marker gene combinations that uniquely define each cell type, providing a foundational resource that enables the design of cell -type-specific genetic reagents. Overall, our study provides fundamental insights into the cellular diversity of sexual circuits and how evolution shapes cell types and gene expression in behavioral adaptations.

evolutionary biology↗

bioRxiv2025

Comparative genomics of DH5α-inhibiting Escherichia coli isolates from human feces reveals common co-occurrence of bacteriocin genes with virulence factors and antibiotic resistance genes.

The presence of multi-drug-resistant (MDR) bacteria in healthy individuals poses a significant public health concern, as these strains may contribute to or even facilitate the dissemination of antibiotic resistance genes (ARGs) and virulence factors. In this study, we investigated the genomic features of antimicrobial-producing Escherichia coli strains from the gut microbiota of healthy individuals in Singapore. Using a large-scale screening approach, we analyzed 3,107 E. coli isolates from 109 fecal samples for inhibitory activity against E. coli DH5 and performed whole-genome sequencing on 37 representative isolates. Our findings reveal genetically diverse strains, with isolates belonging to five phylogroups (A, B1, B2, D, and F) and 23 unique sequence types (STs). Bacteriocin gene clusters were widespread, with colicins and microcins dominating the profiles. Notably, we identified a hcp-et3-4 gene cluster, encoding an effector linked to Type VI secretion system. Approximately 40% of the sequenced isolates were MDR, with resistance for up to eight antibiotic classes in one strain. Plasmids were the primary vehicles for ARG dissemination, but chromosomal resistance determinants were also detected. Additionally, over 55% of isolates were classified as potential extraintestinal pathogenic E. coli (ExPEC), raising concerns about their potential pathogenicity outside the intestinal tract. Our study highlights the co-occurrence of bacteriocins, ARGs, and virulence genes in gut-residing E. coli, underscoring their potential role in shaping microbial dynamics and antibiotic resistance. While bacteriocin-producing strains show potential as probiotic alternatives, careful assessment of their safety and genetic stability is necessary for therapeutic applications. ImportanceThis study provides genomic insights into the diverse repertoire of potential bacteriocin production in E. coli strains isolated from a cohort of healthy human subjects in Southeast Asia. Our findings suggest that the co-occurrence of bacteriocin genes with multiple antibiotic resistance and virulence genes is a common feature among non-clinical isolates. This genetic linkage could contribute to the increased abundance of multi-drug-resistant and virulent strains within individual hosts. Moreover, this co-occurrence may facilitate the host colonization with strains carrying antibiotic resistance and virulence determinants, potentially also contributing to the dissemination of resistant and pathogenic strains within the local population and beyond.

microbiology↗

bioRxiv2025

G-Quadruplexes Act as an On/Off Switch While i-Motifs Regulate Insulin Expression in Reporter Gene Assays

The insulin-linked polymorphic region (ILPR) is a variable number tandem repeat located in the promoter of the human insulin gene. This G-rich sequence can fold into four-stranded G-quadruplex DNA structures, while its complementary C-rich strand forms i-motifs. The ILPR varies in repeat number and sequence composition, but the relationship between sequence diversity, DNA structure, and insulin gene regulation remains poorly understood. Although both G-quadruplexes and i-motifs have been implicated in transcriptional control, their relative contributions, particularly when formed on complementary strands of the same locus, are unclear. Here, we characterised the structure and stability of nine ILPR-based sequences using biophysical techniques and luciferase reporter assays. We demonstrate that transcriptional activation in response to high glucose occurs only when both G-quadruplex and i-motif structures can form. Other combinations of structures do not induce transcription. Moreover, promoter activity correlated positively with i-motif stability, but not with G-quadruplex stability. These results suggest a model in which G-quadruplexes function as an on/off switch, while i-motifs act as modulators of gene expression. Our findings underscore the importance of treating G-quadruplexes and i-motifs as a dynamic, interdependent system in both the regulation of gene expression and also the potential of these structures as therapeutic targets. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/651924v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@16ae322org.highwire.dtl.DTLVardef@65e893org.highwire.dtl.DTLVardef@884ab3org.highwire.dtl.DTLVardef@1e0311e_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2025

Biosynthesis and Physiological Significance of Organ-Specific Flavonol Glycosides in Solanaceae

Flavonols are subclasses of flavonoids, with hundreds of structures identified in plants. This chemical diversity primarily arises from glycosylation, where sugars are selectively added to the flavonol backbone. While flavonol profiles vary across species and organs, the evolutionary forces shaping this chemodiversity and the physiological significance of specific glycosides remain a mystery. Here, we reveal that finely tuned transcriptional regulation and the sugar selectivity of glycosyltransferases drive the formation of distinct organ specific flavonol profiles and a specific flavonol is necessary for male fertility. In Solanaceae pollen, two flavonol glycosides, K2 (kaempferol 3-O-glucosyl(1 [->] 2)galactoside) and Q2 (quercetin 3-O-glucosyl(1 [->] 2)galactoside), are exclusively accumulated. K2 is evolutionarily conserved, while Q2 was lost over time. Consistently, K2 is essential for male fertility, whereas Q2 and aglycones fail to rescue fertility defects. These findings suggest that individual flavonol glycosides have distinct physiological roles, either actively maintained or discarded through evolutionary selection.

plant biology↗

bioRxiv2025

Identifying Key Cells for Fibrosis by Systematically Calling Cell Type-Phenotype Associations across Massive Heterogenous Datasets

Fibrotic diseases pose a significant burden on health care, yet the key pathogenic fibroblasts involved remain unclear. We developed the fibrotic disease fibroblast atlas (FDFA), which comprises 394 single-cell and 38 spatial transcriptomic samples from 11 common fibrotic diseases. To perform a cell-type phenotype association study in large-scale heterogeneous datasets, we developed the single-cell phenotype association research kit for large-scale dataset exploration (SPARKLE). SPARKLE handles heterogeneity by incorporating confounding information into its generalized linear mixed models (GLMMs). The application of SPARKLE to FDFA revealed that matrix fibroblasts (MTFs) constitute a crucial pathogenic cell group in fibrosis. Their increased proportion correlate with the fibrotic process. MTFs also synergize with MYO-Fs, increasing their degree of fibrosis. Based on MTF, we identified 25 potential antifibrotic targets for broad-spectrum antifibrotic therapies. This study enhances our understanding of fibrosis and provides a reliable framework for large-scale cell type-phenotype association research. HighlightsO_LIA cross-tissue, multidisease fibrotic disease fibroblast atlas (FDFA) reveals diverse fibroblast subtypes in fibrosis diseases. C_LIO_LIA new toolkit, SPARKLE, is introduced for detecting robust cell type-phenotype associations in large-scale heterogeneous datasets. C_LIO_LIMultiple pathogenic fibroblasts associated with common fibrosis disease (MTF) onset and progression have been identified, suggesting potential cell-specific therapeutic strategies for fibrosis-related diseases. C_LI

bioinformatics↗

bioRxiv2025

Sex-specific and age-related progression of auditory neurophysiological deficits in the Cln3 mouse model of Batten disease

CLN3 disease is a prevalent form of Neuronal Ceroid Lipofuscinosis (NCL) caused by inherited mutations in the CLN3 gene, with symptoms such as vision loss, language impairment, and cognitive decline. The early onset of visual deficits complicates neurological assessment of brain pathophysiology underlying cognitive decline, while the small number of CLN3 mutation cases in humans hinders the study of sex differences. Building on our recent progress in assessing auditory neurophysiological changes in CLN3 patients, we developed a parallel approach using electroencephalography arrays in Cln3 knockout (Cln3-/-) mice to investigate the longitudinal progression of auditory processing deficits in both sexes. We employed a duration mismatch negativity (MMN) paradigm, similar to that used in our CLN3 patient studies, to assess the automatic detection of pattern changes in a sequence of stimuli. Wild-type mice of both sexes showed robust duration MMN responses when assessed longitudinally in the same subjects from 3 to 9 months of age. In contrast, female Cln3-/- mice developed consistent MMN deficits throughout this age range, while male Cln3-/- mice exhibited MMN deficits at younger ages that were mitigated at older ages. Analyses of auditory brainstem responses indicate that MMN abnormalities in Cln3-/- mice are not due to peripheral hearing loss. Instead, these deficits originate centrally from sex-specific and age-related changes in auditory evoked potentials elicited by standard and deviant stimuli. Our findings reveal a sex-specific progression of central auditory processing deficits in Cln3-/- mice, supporting auditory duration MMN as a translational neurophysiological biomarker for mechanistic studies and therapeutic development. Significance StatementCLN3 disease is an inherited neurodegenerative disorder with progressive decline in cognitive functioning and verbal abilities. The neuropathophysiological mechanisms underlying this decline remain poorly understood, highlighting the urgent need for objective neurological biomarkers to advance mechanistic insights and therapeutic development. Our identification of central auditory processing and change detection deficits in Cln3-/- mice, mirroring findings from our recent studies in CLN3 patients, validates auditory MMN as a translational neurophysiological biomarker bridging pre-clinical and clinical research. Moreover, our discovery of sex-specific, non-linear progression of MMN deficits emphasizes the necessity of developing disease management strategies tailored to each sex. This finding also provides a foundation for investigating both pathogenic and compensatory neural mechanisms to inform the development of individualized treatments.

neuroscience↗

bioRxiv2025

NOD1 ligand FK565 promotes atherogenesis and accumulation of NOD1high smooth muscle cells in atherosclerotic lesions

AimsNucleotide-binding oligomerization domain-containing protein (NOD)1 is an intracellular pattern recognition receptor that initiates immune responses upon ligation of molecules such as bacterial peptidoglycan containing a D-glutamyl-meso-diaminopimelic acid (iE-DAP) moiety. NOD1 ligation has been shown to promote vascular inflammation and atherosclerosis. In this study, we investigate the functional role of NOD1 in atherosclerotic plaques and characterize the vascular cells responsible for NOD1 expression and function. Methods and resultsNOD1 was mainly expressed in a subtype of vascular smooth muscle cells (SMC) in human atherosclerotic lesions. In ex vivo cultures, human endarterectomy specimens reacted to NOD1 ligand by activation of mitogen-activated protein kinase (MAPK) pathways, leading to cytokine expression. Levels of NOD1 mRNA were higher in carotid endarterectomy specimens obtained from symptomatic patients compared to asymptomatic ones. NOD1high SMC were also found in arteries of atherosclerosis-prone Ldlr-/- mice. Challenging these mice with a NOD1 agonist resulted in transmural vascular inflammation, severe arterial damage, accelerated atherogenesis throughout the aorta, and evidence of occlusive coronary artery disease. In rats, mechanic injury to carotid arteries promoted NOD1high SMC expansion and neointima formation. In vitro, neointima derived NOD1high SMCs responded to NOD1 ligand exposure by enhanced migration, increased iNOS+ cells and amplified CCL5 production. ConclusionOur findings show that NOD1 promotes vascular inflammation, vascular injury responses and atherosclerosis by acting on a NOD1high subtype of SMC.

immunology↗

bioRxiv2025

GlycoGenius: the ultimate high-throughput glycan composition identification tool

Mass spectrometry is recognized as the gold standard for glycan analysis, yet the complexity of generated data hampers progress in glycobiology, as existing tools lack full automation, requiring extensive manual effort. We introduce GlycoGenius, an open-source program offering an automated workflow for glycomics data analysis, featuring an intuitive graphical interface. With algorithms tailored to reduce manual workload, it allows for data visualization and automatically constructs search spaces, identifies, scores, and quantifies glycans, filters results, and annotates fragment spectra of N- and O-glycans, glycosaminoglycans and more. It seamlessly guides researchers of all expertise levels from raw data to publication-ready figures. Our findings demonstrate that GlycoGenius achieves results comparable with manual analysis or competing tools, identifying more glycans, including novel ones, while significantly reducing processing time. This groundbreaking tool represents a significant advancement in the study of glycoconjugates, empowering researchers to focus on insights rather than data processing.

bioinformatics↗

bioRxiv2025

Targeted genome mining with GATOR-GC maps the evolutionary landscape of biosynthetic diversity

Gene clusters, groups of physically adjacent genes that work collectively, are pivotal to bacterial fitness and valuable in biotechnology and medicine. While various genome mining tools can identify and characterize gene clusters, they often overlook their evolutionary diversity, a crucial factor in revealing novel cluster functions and applications. To address this gap, we developed GATOR-GC, a targeted genome mining tool that enables comprehensive and flexible exploration of gene clusters in a single execution. We show that GATOR-GC identified a diversity of over 4 million gene clusters similar to experimentally validated biosynthetic gene clusters (BGCs) that other tools fail to detect. To highlight the utility of GATOR-GC, we identified previously uncharacterized co-occurring conserved genes potentially involved in mycosporine-like amino acid biosynthesis and mapped the taxonomic and evolutionary patterns of genomic islands that modify DNA with 7-deazapurines. Additionally, with its proximity-weighted similarity scoring, GATOR-GC successfully differentiated BGCs of the FK-family of metabolites (e.g., rapamycin, FK506/520) according to their chemistries. We anticipate GATOR-GC will be a valuable tool to assess gene cluster diversity for targeted, exploratory, and flexible genome mining. GATOR-GC is available at https://github.com/chevrettelab/gator-gc. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/639861v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@6bf054org.highwire.dtl.DTLVardef@6f3eeaorg.highwire.dtl.DTLVardef@18ba201org.highwire.dtl.DTLVardef@3928dd_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

DeepMM: Identify and correct Metagenome Misassemblies with deep learning

Accurate metagenomic assemblies are essential for constructing reliable metagenome-assembled genomes (MAGs). However, the complexity of microbial genomes continues to pose challenges for accurate assembly. Current reference-free assembly evaluation tools primarily rely on hand-crafted features and suffer from poor generalization across different metagenomic data. To address these limitations, we propose DeepMM, a novel deep learning-based visual model de-signed for the identification and correction of metagenomic misassemblies. DeepMM transforms alignments between assemblies and reads into a multi-channel image for misassembly feature learning and applies contrastive learning to bring different views of misassemblies closer. Fur-thermore, DeepMM offers a fine-tuning process to match different sequencer data. Our results show that DeepMM outperforms state-of-the-art methods in identifying misassemblies, achieving the highest AUPRC score in five CAMI datasets. DeepMM provides accurate correction of misassemblies, significantly improving downstream binning results, increasing the number of near-complete MAGs from 905 to 1006 in a large real metagenomic sequencing dataset derived from a diarrhea-predominant Irritable Bowel Syndrome (IBS-D) cohort.

bioinformatics↗

bioRxiv2025

Unprecedented Cytotoxicity of Transition Metal Metallacarboranes on Triple Negative Breast Cancer Cells and a Vertebrate Cancer Model

Metallacarboranes have long been the subject of attention in the context of medicinal chemistry because of their promising characteristics and unconventional interactions with biological entities. The metal centre has been shown to have a significant influence on the internalisation and cytotoxicity of compounds in human cell lines. Additionally, specific nanomolar concentrations of metallacarboranes have demonstrated toxic effects on MDA-MB-231 cells under in vitro and in vivo conditions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/635527v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@116eb95org.highwire.dtl.DTLVardef@1c4a181org.highwire.dtl.DTLVardef@474c3forg.highwire.dtl.DTLVardef@dec88c_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

EEG-Informed fMRI Analysis Reveals Neurovascular Coupling in Motor Execution and Imagery

The complementary strengths of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) have driven extensive research into integrating these two noninvasive modalities to better understand the neural mechanisms underlying cognitive, sensory, and motor functions. However, the precise neural patterns associated with motor functions, especially imagined movements, remain unclear. Specifically, the correlations between electrophysiological responses and hemodynamic activations during executed and imagined movements have not been fully elucidated at a whole-brain level. In this study, we employed an EEG-informed fMRI approach on concurrent EEG-fMRI data to map hemodynamic changes associated with dynamic EEG temporal features during motor-related brain activities. We localized and differentiated the hemodynamic activations corresponding to continuous EEG temporal dynamics across multiple motor execution and imagery tasks. Validation against conventional block fMRI analysis demonstrated high precision in identifying regions specific to motor activities, underscoring the accuracy of the EEG-driven model. Beyond the expected sensorimotor activations, the integrated analysis revealed supplementary coactivated regions showing significant negative covariation between blood oxygenation level-dependent (BOLD) activities and sensorimotor EEG alpha power, including the cerebellum and insular cortex. These findings confirmed both the colocalization of EEG and fMRI activities in sensorimotor regions and a negative covariation between EEG alpha band power and BOLD changes. Moreover, the results provide novel insights into neurovascular coupling during motor execution and imagery on a brain-wide scale, advancing our understanding of the neural dynamics underlying motor functions. HighlightsO_LIMovement-related EEG alpha activity negatively covaries with BOLD responses C_LIO_LIEEG-informed fMRI maps the neurovascular correlates across the entire brain C_LIO_LIA unified model disentangles multiple motor-related brain activations C_LIO_LIEEG-informed fMRI results highly overlap with conventional block fMRI results C_LI

neuroscience↗

bioRxiv2025

The ift140-Deficient Zebrafish: A Model for Renal Cystogenesis and an F0-Based Screen to Identify Genetic Modifiers of Kidney Cysts

Genetic modifiers are believed to play an important role in the onset and severity of polycystic kidney disease (PKD), but identifying these modifiers has been challenging due to the lack of effective methodologies. In this study, we investigated zebrafish mutants of IFT140, a newly identified ADPKD gene, and observed phenotypes similar to those seen in mammalian models, including kidney cysts and bone defects. Using efficient microhomology-mediated end joining (MMEJ)-based genome editing technology, we demonstrated that ift140 CRISPRants recapitulate mutant phenotypes while bypassing the early lethality of the mutants to allow for renal cyst analysis in adult fish. In addition to cilia defects, non-cilia phenotypes, such as disrupted cell polarity and aberrant microtubule stabilization in kidney epithelial cells, may also contribute to ift140-associated cystogenesis. Importantly, the ability to detect ift140-associated renal cysts with ease allowed us to develop an F0-based genetic screen to identify potential protective modifiers. A pilot screen of sixteen genes previously linked to dysregulated signaling pathways in ADPKD revealed both known and novel modifiers, including mtor and ulk1a. Inhibition of mtor and ulk1a reversed both cilia-related and non-cilia-related abnormalities. In summary, our study underscores the potential of using zebrafish as a model for the efficient discovery of genetic modifiers of kidney cysts.

genetics↗

bioRxiv2025

A Geometric Optical Analysis of Human Retinal Cells and the Hypothesis of Monocular Stereoscopic Vision

We propose a geometric optical model that describes real-image formation via monocular vision in three dimensions. We only assume that the ganglion cell nuclei, bipolar cell nuclei, and photoreceptor cell nuclei in the human retina can be treated as microlenses and actively participate in imaging. In particular, we suggest that monocular vision operates via an array of high-magnification micro-real-image telescopes oriented in various azimuthal directions. The main elements of each telescope are the following. The first is the cornea and crystalline lens, which serve as objective lenses with tunable focal lengths. The second is a paired array of ganglion cell nuclei and bipolar cell nuclei, which act as a conjugate mirror. The third is an individual photoreceptor cell nuclei (cone or rod nuclei), which function as a micro-eyepiece. The fourth is the outer segment of each photoreceptor cell, which serves as a micro-object-distance sensor. We also hypothesize that six combinations of conjugate mirrors and micro-eyepiece arrays work within the human eye. Each combination is responsible for perceiving different ranges of object distances. We further hypothesize that the process by which one human eye perceives object distances involves two stages: from near to finite distances, and from finite distances to infinite distances. In different stages, the distance between different optical elements is tuned so that the object distance can be computed a specific formula when the photocurrent at the retina photoreceptors outer segment layer vanishes. Lastly, we conduct computational simulations. We find that there are two possible processes. By tuning the distances between the elements of our optical model, the eye can perceive object distances as close as 25 cm to dozens of meters in one process and dozens of meters to kilometers in the other process, depending on the sensitivity of the eye to small changes in focal plane spacing.

physiology↗

bioRxiv2024

High-Throughput Quantification of miRNA-3'-Untranslated-Region Regulatory Effects

MicroRNAs (miRNAs) regulate gene expression post-transcriptionally, primarily through binding sites in 3' untranslated regions (3' UTRs). While computational and biochemical approaches have been developed to predict miRNA binding sites on target messenger RNAs, reliable and high-throughput assessment of the regulatory effects of miRNAs on full-length 3' UTRs can still be challenging. Utilizing a miniaturized and high-throughput reporter assay, we present a pilot miRNA-targeting map, containing 4,994 successfully measured miRNA:3' UTR regulatory outputs by pairwise assays between 461 miRNAs and eleven 3' UTRs. This collection represents a large experimental miRNA:3' UTR dataset to date on a single platform. The methodology can be generally applied to studies of miRNA-mediated regulation of critical genes. We found that seedless sites can lead to substantial downregulation. We utilized this dataset in the development of a quantitative total score for modeling the total regulatory effects by both seed and seedless sites on a full-length 3' UTR. To assess the predictive value of the total score, we analyzed data from mRNA expression and proteomics studies. We found that the score can discriminate the potent miRNA inhibition from the weak inhibition and is thus useful for quantitative prediction of miRNA regulation. The score has been added to the STarMir program of the Sfold package now available via GitHub at https://github.com/Ding-RNA-Lab/Sfold.

molecular biology↗

bioRxiv2024

Isoliquiritigenin attenuated cognitive impairment, cerebral tau phosphorylation and oxidative stress in a streptozotocin-induced mouse model of Alzheimers disease

IntroductionTau hyperphosphorylation, mitochondrial dysfunction and oxidative stress play important roles in Alzheimers disease (AD). Isoliquiritigenin, a natural flavonoid isolated from the root of liquorice, has been shown to exert inhibitory effects on oxidative stress. Here, we assessed the neuroprotective effects of isoliquiritigenin on a streptozotocin-injected mouse model. MethodMolecular docking analysis performed for isoliquiritigenin with mTOR and ERK2. The mice (n = 27, male) were intracerebroventricularly injected with streptozotocin, treated with isoliquiritigenin (intraperitoneal, 2 days) and assessed using the Morris water maze. Oxidative stress, tau phosphorylation, mitochondrial dysfunction and synaptic impairment were evaluated in the cortex and hippocampal tissues of the mice by using biochemical assays and immunofluorescence staining. ResultsIsoliquiritigenin treatment mitigated the spatial memory capacity of streptozotocin-injected mice and alleviated tau phosphorylation at Ser396; the production of reactive oxygen species; the mitochondrial fission proteins Mfn1 and Mfn2; neuronal loss; and synaptic impairment (PSD95, SNAP25). Isoliquiritigenin treatment reduced the levels of mTOR Ser2448 and ERK1/2 T202/Y204 and upregulated the level of GSK-3{beta}Ser9 in the cortex and hippocampus of streptozotocin-injected mice. ConclusionIn conclusion, our findings suggest that isoliquiritigenin ameliorates streptozotocin-induced cognitive impairment, hyperphosphorylated tau, oxidative stress, mitochondrial dysfunction and synaptic impairment by decreasing mTOR and ERK activity and increasing GSK-3{beta} activity.

neuroscience↗

bioRxiv2024

mTOR inhibition alleviated tau phosphorylation-induced mitochondrial impairment, oxidative stress, and cognitive impairment

AimHyperphosphorylated tau is a hallmark of Alzheimers disease (AD). However, whether mammalian target of rapamycin (mTOR) directly regulates tau phosphorylation at Ser214, Ser356, and Thr231 and how such regulation affects mitochondrial function remain unclear. In this study, we aimed to determine whether mTOR-mediated tau phosphorylation disrupts mitochondrial and metabolic profiles and cognitive function and whether these effects can be reversed by the mTOR inhibitor rapamycin. MethodsTau3E-overexpressing mice were generated by bilateral injection of adeno-associated virus vectors encoding the phosphomimetic TauS214E/T231E/S356E (Tau3E) variant into the hippocampal CA3 region of 2-month-old C57BL/6 mice. The mice received intraperitoneal rapamycin for one week. Cognitive performance was assessed using the Morris water maze. MALDI-mass spectrometry imaging was conducted to evaluate metabolic alterations in the brain tissue slices. mTOR, p70S6K, and tau phosphorylation protein expression; mitochondrial dynamics markers; and reactive oxygen species (ROS) levels were analyzed by Western blotting, immunofluorescence, and flow cytometry in HT22 cells, Tau3E mice, and postmortem AD brain tissues. ResultsPhosphorylated mTORS2448 colocalized with p-TauSer214, p-TauSer356, and p-TauThr231 in the hippocampal CA3 region of AD brains. HT22 cells and Tau3E mice exhibited increased levels of p-mTOR, p-p70S6K, and ROS production; mitochondrial fragmentation; and tau phosphorylation at Ser214, Ser356, and Thr231. Rapamycin treatment partially ameliorated cognitive deficits, reduced oxidative stress and mitochondrial dysfunction, and restored metabolic profile particularly the inosine-pentose phosphate pathway-glycolysis metabolic axis, structural lipidome axis and the neurotransmitter homeostasis. ConclusionmTOR activation contributes to site-specific tau hyperphosphorylation, mitochondrial dysfunction, and cognitive impairment. Pharmacological inhibition of mTOR by rapamycin attenuated tau pathology, regulated metabolic alterations, preserved mitochondrial homeostasis, and improved cognitive function, suggesting a potential therapeutic strategy for AD.

neuroscience↗