Biology subjects

Jiao, Y.

Publications and source records attributed to Jiao, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Cell cycle-driven epigenetic resetting maintains stem cell fate for shoot branching

Adult mammalian stem cells typically maintain stem cell identity through proliferative quiescence. In contrast, we demonstrate that stem cell maintenance in Arabidopsis bud precursor cells requires active cell-cycle progression. Inhibiting division silences the shoot meristem marker gene SHOOT MERISTEMLESS (STM) and promotes differentiation. Whereas proliferation dilutes H3K27me3 levels to counteract silencing. Meanwhile, we identified two classes of transcription factors recruiting polycomb repressive complex 2 (PRC2) to epigenetically silence STM. The balance between these forces establishes a cell cycle-coupled epigenetic "Sisyphus" mechanism that maintains pluripotency. This cell fate switch is bistable; modeling and experimental data confirm that prolonged quiescence triggers irreversible differentiation. We propose that sequence-dependent PRC2 recruitment in plants enables precise silencing of fate-determining genes, while cell proliferation sustains pluripotency by resetting epigenetic marks.

plant biology↗

bioRxiv2025

Deep Learning of Brain-Behavior Dimensions Identifies Transdiagnostic Biotypes in Youth with ADHD and Anxiety Disorders

Attention-deficit/hyperactivity disorder and anxiety disorders are highly prevalent in youth and are characterized by substantial heterogeneity and frequent co-occurrence. This transdiagnostic complexity challenges conventional diagnostic frameworks that rely on symptom-based categories, which often obscure underlying dimensional and neurobiological mechanisms and offer limited neurobiological specificity. To address these issues, we developed a deep learning-based brain-behavior modeling framework that integrates clinically salient functional connectivity with cognitive and behavioral measures to identify interpretable dimensions and biologically grounded subtypes (biotypes). We applied our model to the Adolescent Brain Cognitive Development (ABCD) dataset comprising 3,508 children aged 9-11 years and revealed two reproducible brain-behavior dimensions that captured variation in cognitive control and emotion-attention regulation. These dimensions further yielded three distinct biotypes, each exhibiting unique symptom profiles and distinct brain development. We tested the robustness and generalizability of the dimensions and corresponding biotypes in an independent cohort of 224 age-matched participants from the Healthy Brain Network (HBN) and documented their early expression before symptom onset during adolescence. These findings highlight the utility of brain-behavior dimensions for elucidating heterogeneous psychiatric presentations and advance a biologically grounded framework for early classification and potential clinical translation in youth mental health.

neuroscience↗

bioRxiv2025

Augmented prediction of multi-species protein--RNA interactions using evolutionary conservation of RNA-binding proteins

AbstractRNA-binding proteins (RBPs) play critical roles in gene expression regulation. Recent studies have begun to detail the RNA recognition mechanisms of diverse RBPs. However, given the array of RBPs studied so far, it is implausible to experimentally profile RBP-binding peaks for hundreds of RBPs in multiple non-model organisms. Here, we introduce MuSIC (Multi-Species RBP-RNA Interactions using Conservation), a deep learning-based framework for predicting cross-species RBP-RNA interactions by leveraging label smoothing and evolutionary conservation of RBPs across 11 diverse species ranging from human to yeast. MuSIC outperforms state-of-the-art computational methods, and provides predicted RBP-binding peaks across species with high accuracy. The prediction confidence is higher in the closely related species, partially due to the RBP conservation patterns. Finally, the effects of homologous genetic variants on RBP binding can be computationally quantified across species, followed by experimental validations. The target transcripts with disrupted binding events are enriched with the ubiquitination-associated pathways. To summarize, MuSIC provides a useful computational framework for predicting RBP-RNA interactions cross-species and quantifying the effects of genetic variants on RBP binding, offering novel insights into the RBP-mediated regulatory mechanisms implicated in human diseases. HighlightsO_LIMuSIC integrates RBP-binding peaks with conservation-weighted label smoothing to predict RBP-RNA interactions across eleven species C_LIO_LIMuSIC outperforms state-of-the-art computational methods in predicting cross-species RBP-RNA interactions C_LIO_LICross-species prediction accuracy of RBP-binding peaks correlates with the conservation of RBPs C_LIO_LIMuSIC quantifies the effects of homologous SNVs on RBP binding with experimental validation in mouse C_LI

bioinformatics↗

bioRxiv2025

Programmable multiplexed phosphosignaling networks in bacteria

Natural bacterial two-component systems use crosstalk between histidine kinases to integrate multiple environmental cues, enabling complex multi-signal decisions. In comparison, most synthetic bacterial phosphosignaling circuits remain confined to single-input designs. Here, we establish a bottom-up framework for phosphosignaling circuits using two histidine kinases (2HKs) that converge on a shared response regulator (RR). As a proof of concept, we built a synthetic 2HK-1RR circuit in Escherichia coli that consists of a blue-light sensor (YF1) and an indole-3-aldehyde sensor, integrating opto- and chemo-signals through their shared RR. By using distinct dimerization tags on each HK, tuning HK activities, and reversing HK response modes, we program a spectrum of logic behaviors. These include ternary gates (an inverse count gate, a count gate, and two context gates), as well as a binary NAND gate. This work establishes fundamental phosphosignaling circuit design rules based on two-component systems that expand the scope of synthetic gene circuit design and pave the way towards complex, multi-input environmental biosensors and programmable therapeutics.

synthetic biology↗

bioRxiv2025

BrainBeacon: A Cross-Species Foundation Model for Single-cell Resolved Brain Spatial Transcriptomics

The brains functional complexity emerges from spatiotemporal heterogeneity in molecular, cellular, and circuit organization, shaped by evolution, aging, and disease. Single-cell spatial transcriptomics provides a transformative framework to decode this complexity, resolving cell-type-specific expression patterns, region-specific regulation, evolutionary divergence, and disease-associated disruptions. Despite recent advances in spatial transcriptomics, a unified foundation model capturing cross-species, whole-brain cellular architecture remains lacking. Here, we introduce BrainBeacon, the first cross-species foundation model for whole-brain spatial transcriptomics. Trained on 133 million spatially resolved cells covering a total area of 210194 mm2 from human, macaque, marmoset and mouse brains profiled across five major platforms, BrainBeacon integrates gene expression rankings, spatial cellular organization, and evolutionarily conserved genetic relationships into a unified transformer-based architecture. A two-stage training strategy captures both intra-cellular transcriptional dependencies and inter-cellular spatial interactions, yielding biologically grounded and interpretable representations of brain structure. Subsequently, BrainBeacon enables cross-species alignment of brain cell types and anatomical regions, facilitating integrative analyses of conserved and divergent cellular architectures. Moreover, it uncovers spatial regulatory mechanisms of aging by predicting bidirectional perturbation responses between cells and their local niche. Together, BrainBeacon serves as a foundational cross-species model for whole-brain spatial transcriptomics, enabling virtual brain atlas construction, systematic in silico perturbation studies, and mechanistic insights into brain disease pathogenesis.

bioinformatics↗

bioRxiv2025

Gut Microbiota Succession and Metabolic Pathway Remodeling in the Progression of Type 2 Diabetes Mellitus in Adult Rats

BackgroundEmerging evidence highlights the complex interplay between gut microbiota and type 2 diabetes mellitus (T2D); however, the temporal trajectory of microbial community succession and the concomitant shifts in associated metabolic pathways across the disease lifecycle remain poorly characterized. In this study, we conducted a multi-dimensional analysis of gut microbiota composition and functional pathways in rats, spanning the continuum from health, through the T2D pathological state, to post-intervention recovery phases. ResultsHealthy aged rats exhibited significantly greater gut microbial diversity compared to both younger healthy cohorts and T2D rats. In the absence of intervention, progressive T2D development led to a sustained decline in microbial diversity that persisted until death. Notably, {beta}-tocotrienol ({beta}-T3), metformin hydrochloride (MET) and healthy dietary interventions not only improved fasting blood glucose (FPG) levels in T2D mice but also restored their gut microbial diversity and metabolic functions. At the phylum level, the ratio of p Bacteroidota to p Firmicutes exhibited an age-dependent increase in healthy rats but displayed a progressive decline in T2D rats. Notably, species-specific expansions were observed across both healthy and pathological states. For example, s Bacteroides_acidifaciens (B. acidifaciens) showed a significant expansion in early T2D stage disease, while s Anaerostipes_hadrus became the dominant species in advanced-stage T2D. Among intervention groups, s Phascolarctobacterium_faecium was enriched in the {beta}-tocotrienol ({beta}-T3) group; the abundance of s Escherichia_coli (E. coli) increased dramatically in the deceased rats. Gut metabolites also exhibited distinct characteristics across different physiological stages. In young rats, the metabolite profile was characterized by lower abundances of most metabolites, which stabilized with age accompanied by upregulation of select molecules in older rats. Notably, during T2D progression, the metabolite profile displayed a largely opposite pattern compared to healthy controls. Importantly, dietary interventions including healthy food, {beta}-T3, MET partially restored metabolic homeostasis in T2D rats. Further analysis revealed that key differential metabolites across groups were enriched in bile acids (BAs), amino acids, benzene and its substituted derivatives, and organic acids with their derivatives. Specifically, amino acid metabolism was more active in healthy rats, whereas BA and benzene derivative metabolism were upregulated in T2D. Key microbial species driving these shifts included s Lactobacillus_johnsonii, s Lactobacillus_reuteri, and B. acidifaciens, which exhibited positive correlations with BAs and select amino acids. The B. acidifaciens could be a biomarker of T2D and glycoursodeoxycholic acid, sohyodeoxycholic acid, beta-muricholic acid and allocholic acid were the key BAs to regulate glycometabolism of the host. ConclusionsDuring the T2D stage, both gut microbiota composition and metabolic profiles exhibited distinct characteristics compared to those of healthy age-matched older rats. Notably, {beta}-T3 and MET interventions not only facilitated the recovery of gut microbial diversity and metabolite levels in T2D mice but also promoted the proliferation of specific dominant species, each intervention favoring distinct taxa. In this context, B. acidifaciens emerged as a dominant bacterial species in T2D, exerting regulatory effects on glycometabolism through BA and amino acid metabolic pathways. Collectively, these findings advance our understanding of T2D pathophysiology and highlight the potential of probiotic-based therapies for its management. ImportanceThe T2D is a kind of chronic disease and the gut microbiota shows a continuously slow succession from some microbial populations to other ones in the disease progress. Uncovering the rule of change in gut bacteria from healthy rats to T2D ones and the recovering capacity of gut microbiota through interventions of healthy food, {beta}-T3 and antidiabetic drug are beneficial to understand the real regulation mechanism of gut bacteria in T2D progress. Then the results lay the foundation of developing probiotics and researching new metabolic therapeutic target of gut microorganisms. In addition, to research the metabolic regulation mechanism of gut bacteria, using multi-omics including microbiomics and metabonomics is an effective way.

microbiology↗

bioRxiv2025

SCRIPT: predicting single-cell long-range cis-regulation based on pretrained graph attention networks

Single-cell cis-regulatory relationships (CRRs) are essential for deciphering transcriptional regulation and understanding the pathogenic mechanisms of disease-associated non-coding variants. Existing computational methods struggle to accurately predict single-cell CRRs due to inadequately integrating causal biological principles and large-scale single-cell data. Here, we present SCRIPT (Single-cell Cis-regulatory Relationship Identifier based on Pre-Trained graph attention networks) that infers single-cell CRRs from transcriptomic and chromatin accessibility data. SCRIPT incorporates two key innovations: graph causal attention networks supported by empirical CRR evidence, and representation learning enhanced through pretraining on atlas-scale single-cell chromatin accessibility data. Validation using cell-type-specific chromatin contact data demonstrates that SCRIPT achieves a mean AUC of 0.9, significantly outperforming state-of-the-art methods (AUC: 0.68). Notably, SCRIPT obtains a threefold improvement in predicting long-range CRRs (>100 Kb) compared to existing methods. Applying SCRIPT to Alzheimers disease and schizophrenia, we establish a framework for prioritizing disease-causing variants and elucidating their functional effects in a cell-type-specific manner. By uncovering molecular genetic mechanisms undetected by existing computational methods, SCRIPT provides a roadmap for advancing genetic diagnosis and target discovery.

bioinformatics↗

bioRxiv2025

Dynamic Pathway of Guanidine-III Riboswitch Folding Revealed by Single-Molecule FRET: Mg2+-Assisted Preorganization and Ligand-Induced Kinetic Trapping

Riboswitches are structured RNA elements that regulate gene expression by sensing and binding small molecules. The guanidine-III riboswitch, a critical bacterial regulator responding to guanidine toxicity, undergoes precise conformational changes that remain poorly characterized at a dynamic, mechanistic level. In this study, we employed single-molecule Forster Resonance Energy Transfer (smFRET) coupled with molecular dynamics (MD) simulations to delineate how the guanidine-III riboswitch transitions among distinct conformational states. We identify three principal states [-] an extended (E-state), a compacted prefolded intermediate (P-state), and a folded pseudoknot structure (F-state) [-] with rapid interconversion in the absence of ligand. Magnesium ions significantly stabilize intermediate states via a cooperative, preorganization mechanism, enhancing ligand binding efficiency. Binding of guanidine drastically suppresses the reverse transitions, kinetically trapping the riboswitch into its active folded state primarily through a conformational selection mechanism, with additional contributions from induced-fit dynamics. This work illuminates the unique dynamic pathway by which the guanidine-III riboswitch integrates ionic and ligand cues, ensuring precise gene regulatory responses in bacteria.

biophysics↗

bioRxiv2025

Reduction of Listeria on stainless steel surfaces is impacted by sanitizer application method

Pathogen cross-contamination during food production is controlled through sanitation. However, sanitizer efficacy is often studied in bench-scale experiments (e.g., submerged coupons in static or stirred sanitizer) which poorly approximate fluid dynamics. This limits our understanding of how effective sanitization is in commercial application. This study paired computational fluid dynamic (CFD) estimates of shear stress during spray application of sanitizer with measurements of Listeria innocua reduction on stainless steel by 100 ppm hypochlorite sanitizer under various application methods. Static submersion of inoculated coupons for 3 s resulted in a log reduction of 2.3 {+/-} 0.1 log CFU. Bench-scale spray application for 3 s had the largest microbial reduction at the point of sanitizer spray impingement (7.5 {+/-} 0.5 log CFU) and directly adjacent to the impingement point (6.4 {+/-} 0.7 log CFU) where shear stress was the highest. Surface locations below the impingement point that only received fluid film sanitizer run-off had a significantly lower microbial reduction of 0.4 {+/-} 0.1 log CFU (p < 0.05). At the pilot scale, sanitizer spray manually applied by operators achieved a 2.5 {+/-} 0.4 log CFU reduction, which was significantly lower than what was achieved during bench-scale spray application (p < 0.05). Microbial reduction from manual operation of spray equipment was also significantly different among operators (p < 0.05). Discrepancies between bench-scale spraying, pilot-scale spraying, and submerged coupons underscores the need for sanitizer validation under realistic conditions to better understand the risk reduction achieved through sanitation programs during food processing.

microbiology↗

bioRxiv2025

Midkine Attenuates Aβ Fibril Assembly and Amyloid Plaque Formation

Proteomic profiling of Alzheimers disease (AD) brains has identified numerous understudied proteins, including midkine (MDK), that are highly upregulated and correlated with A{beta} since the early disease stage, but their roles in disease progression are not fully understood. Here we present that MDK attenuates A{beta} assembly and influences amyloid formation in the 5xFAD amyloidosis mouse model. MDK protein mitigates fibril formation of both A{beta}40 and A{beta}42 peptides in Thioflavin T fluorescence assay, circular dichroism, negative stain electron microscopy, and NMR analysis. Knockout of Mdk gene in 5xFAD increases amyloid formation and microglial activation. Further comprehensive mass spectrometry-based profiling of whole proteome and detergent-insoluble proteome in these mouse models indicates significant accumulation of A{beta} and A{beta}-correlated proteins, along with microglial components. Thus, our structural and mouse model studies reveal a protective role of MDK in counteracting amyloid pathology in Alzheimers disease.

biochemistry↗

bioRxiv2025

Mosquito Cell Atlas: A single-nucleus transcriptomic atlas of the adult Aedes aegypti mosquito

The female Aedes aegypti mosquitos remarkable ability to hunt humans and transmit pathogens relies on her unique biology. Here, we present the Aedes aegypti Mosquito Cell Atlas, a comprehensive single-nucleus RNA sequencing dataset of more than 367,000 nuclei from 19 dissected tissues of adult female and male Aedes aegypti, providing cellular-level resolution of mosquito biology. We identify novel cell types and expand our understanding of sensory neuron organization of chemoreceptors to all sensory tissues. Our analysis uncovers male-specific cells and sexually dimorphic gene expression in the antenna and brain. In female mosquitoes, we find that glial cells in the brain, rather than neurons, undergo the most extensive transcriptional changes following blood feeding. Our findings provide insights into the cellular basis of mosquito behavior and sexual dimorphism. The Aedes aegypti Mosquito Cell Atlas resource enables systematic investigation of cell type-specific expression across all mosquito tissues.

genomics↗

bioRxiv2025

Evidence for evolution of a new sex chromosome within the Marchantiales haploid plant lineage

Sex chromosomes have evolved independently in numerous lineages across the tree of life, in both diploid-dominant species, including many animals and plants, and the less studied haploid-dominant plants and algae. Strict genetic sex determination ensures that individuals reproduce by outcrossing. However, species with separate sexes (termed dioecy in diploid plants, and dioicy in haploid plants) may sometimes evolve different sex systems, and become monoicous, with the ability to self-fertilize. Here, we study dioicy-monoicy transitions in the ancient liverwort haploid plant lineage, using three telomere-to-telomere gapless chromosome-scale reference genome assemblies from the Ricciaceae group of Marchantiales. Ancestral liverworts are believed to have been dioicous, with U and V chromosomes (chromosome 9) determining femaleness and maleness, respectively. We confirm the finding that monoicy in Ricciocarpos natans evolved from a dioicous ancestor, and most ancestrally U chromosomal genes have been retained on autosomes in this species. We also describe evidence suggesting the possible re-evolution of dioicy in the genus Riccia, with probable de novo establishment of a sex chromosome from an autosome (chromosome 5), and further translocations of genes from the new sex chromosome to autosomes. Our results also indicated that m-chromosomes are consistent genomic features, and may have evolved independently from sex chromosomes in Ricciocarpos and Riccia lineages.

evolutionary biology↗

bioRxiv2025

Food pairing independently associated with cardiometabolic traits beyond dietary patterns across western and eastern populations

Cardiometabolic health is closely linked to diet. Both specific food choices and dietary indices are commonly used to guide cardiometabolic protection strategies. However, the balance between foods may also significantly impact cardiometabolic health. Here, we explore the balance and imbalance in long-term dietary food intake to quantify food pairing patterns (FPs), providing insights beyond conventional dietary indices and single-food intake frequencies. Using data from our GGMP (n = 6,994) and the NHANES (n = 7,350) cohorts, we observed that long-term food pairing patterns are independent of single food intake frequency and dietary indices. We identified 1,759 and 306 cardiometabolic-related long-term food pairing patterns from two cohorts (FDR < 0.05), respectively. Notably, around 80% of these pairing foods not individually associated with cardiometabolic traits, and food pairing pattern associations with cardiometabolic traits at hyper food group level were consistent across Eastern and Western populations. Besides, mediation analysis revealed that 72.7% of long-term food pairing patterns affected cardiometabolic traits through 31 microbial genera, with Clostridiumsensustricto1 playing a predominant role. Moreover, multi-step mediation analysis found that microbes mediated the impact of long-term food pairing patterns on cardiometabolic traits primarily through their metabolic pathways, such as pyruvate fermentation to propanoate and ergothioneine biosynthesis pathways. Our data suggest that balance between dietary foods is broadly associated with cardiometabolic traits by modulating gut microbial functionalities, in contrast to the lower occurrence when considering individual foods in isolation. These results offer a novel perspective for designing personalized dietary strategies beyond present dietary indices to enhance cardiometabolic health.

microbiology↗

bioRxiv2024

The genetic diversity and populational specificity of the human gut virome at single nucleotide resolution

Large-scale characterization of gut viral genomes provides strain-resolved insights into host-microbe interactions. However, existing viral genomes are mainly derived from Western populations, limiting our understanding of global gut viral diversity and functional variations necessary for personalized medicine and addressing regional health disparities. Here, we introduce the Chinese Gut Viral Reference (CGVR) set, consisting of 120,568 viral genomes from 3,234 deeply sequenced fecal samples collected nationwide, covering 72,751 viral species-level clusters (VSCs), nearly 90% of which are absent from current databases. Analysis of single nucleotide variations (SNVs) in 233 globally prevalent VSCs revealed that 18.9% showed significant genetic stratification between Chinese and non-Chinese populations, potentially linked to bacterial infection susceptibility. The predicted bacterial hosts of population-stratified viruses exhibit distinct genetic components associated with health-related functions, including multidrug resistance. Additionally, viral strain diversity at the SNV level correlated with human phenotypic traits, such as age and gastrointestinal issues like constipation. Our analysis also indicates that the human gut bacteriome is specifically shaped by the virome, which mediates associations with human phenotypic traits. This foundational resource underscores the unique genetic makeup of the gut virome across populations and emphasizes the importance of recognizing gut viral genetic heterogeneity for deeper insights into regional health implications.

microbiology↗

bioRxiv2024

SUMO E1 covalent allosteric inhibitors modulate polyamine synthesis via the MAT2A-AdoMetDC axis

Upregulation of protein SUMOylation is associated with various diseases, and SUMOylation inhibitors are promising drug candidates. We performed the first virtual screening of SUMO E1 covalent allosteric inhibitors (CAIs) and identified two SUMO E1 CAIs with new scaffolds and covalent warheads. We further demonstrated that these new CAIs perturbed the SUMOylation pathway and protein SUMOylation. Specifically, these CAIs affected the SUMOylation of the methionine adenosyltransferases MAT2A. The inhibition of MAT2A SUMOylation unexpectedly stimulated polyamine synthesis. Lastly, we showed that the combination of SUMO E1 CAIs with a polyamine synthesis inhibitor had synergistic effects in inhibiting T47D cells. Our work demonstrated the first cost-effective virtual screening of SUMO E1 CAIs, found that the downregulation of MAT2A SUMOylation increases polyamine synthesis, and SUMO E1 CAIs can synergize with polyamine synthesis inhibitors. This work would be of great value to the study of SUMOylation, covalent/allosteric drugs, and the polyamine metabolism network.

pharmacology and toxicology↗

bioRxiv2024

Spotiphy enables single-cell spatial whole transcriptomics across the entire section

Spatial transcriptomics (ST) has advanced our understanding of tissue regionalization by enabling the visualization of gene expression within whole tissue sections1, but the approach remains dogged by the challenge of achieving single-cell resolution without sacrificing whole genome coverage2,3. Here we present Spotiphy (Spot imager with pseudo single-cell resolution histology), a novel computational toolkit that transforms sequencing-based ST data into single-cell-resolved whole-transcriptome images. In evaluations with Alzheimers disease (AD) and normal mouse brains, Spotiphy delivers the most precise cellular compositions. For the first time, Spotiphy reveals novel astrocyte regional specification in mouse brains. It distinguishes sub-populations of DAM (Disease-Associated Microglia) located in different AD mouse brain regions. Spotiphy also identifies multiple spatial domains as well as changes in the patterns of tumor-tumor microenvironment interactions using human breast ST data. Spotiphy enables visualization of cell localization and gene expression in tissue sections, offering key insights into the function of complex biological systems.

systems biology↗

bioRxiv2024

Creating overlapping genes by alternate-frame insertion

Overlapping genes-wherein two different proteins are translated from alternative frames of the same DNA sequence-provide a means to stabilize an engineered gene by directly linking its evolutionary fate with that of an overlapped gene. However, creating overlapping gene pairs is challenging as it requires redesign of both protein products to accommodate overlap constraints. Here, we present a new "overlapping, alternate-frame insertion" (OAFI) method for creating overlapping genes by insertion of an "inner" gene, encoded in an alternate frame, into a flexible region of an "outer" gene. Using OAFI, we create new overlapping gene pairs of bacterial toxins within an antibiotic resistance gene. We show that both the inner and outer genes retain functionality despite redesign, with translation of the inner gene is influenced by its overlap position in the outer gene. Additionally, we show that selection for the outer gene alters the permitted inactivating mutations in the inner gene and that overlapping toxins can restrict horizontal gene transfer of the antibiotic resistance gene. Overall, OAFI offers a versatile tool for synthetic biology, expanding the applications of overlapping genes in gene stabilization and biocontainment.

synthetic biology↗

bioRxiv2024

Human-mouse proteomics reveals the shared pathways in Alzheimer's disease and delayed protein turnover in the amyloidome

Murine models of Alzheimers disease (AD) are crucial for elucidating disease mechanisms but have limitations in fully representing AD molecular complexities. We comprehensively profiled age-dependent brain proteome and phosphoproteome (n > 10,000 for both) across multiple mouse models of amyloidosis. We identified shared pathways by integrating with human metadata, and prioritized novel components by multi-omics analysis. Collectively, two commonly used models (5xFAD and APP-KI) replicate 30% of the human protein alterations; additional genetic incorporation of tau and splicing pathologies increases this similarity to 42%. We dissected the proteome-transcriptome inconsistency in AD and 5xFAD mouse brains, revealing that inconsistent proteins are enriched within amyloid plaque microenvironment (amyloidome). Determining the 5xFAD proteome turnover demonstrates that amyloid formation delays the degradation of amyloidome components, including A{beta}-binding proteins and autophagy/lysosomal proteins. Our proteomic strategy defines shared AD pathways, identify potential new targets, and underscores that protein turnover contributes to proteome-transcriptome discrepancies during AD progression.

biochemistry↗