PubMed

EMBO J. 2025 Jan 3. doi: 10.1038/s44318-024-00335-7. Online ahead of print.ABSTRACTMitochondrial carrier homolog 2 (MTCH2) is a regulator of apoptosis, mitochondrial dynamics, and metabolism. Loss of MTCH2 results in mitochondrial fragmentation, an increase in whole-body energy utilization, and protection against diet-induced obesity. In this study, we used temporal metabolomics on HeLa cells to show that MTCH2 deletion results in a high ATP demand, an oxidized cellular environment, and elevated utilization of lipids, amino acids, and carbohydrates, accompanied by a decrease in several metabolites. Lipidomics analysis revealed a strategic adaptive reduction in membrane lipids and an increase in storage lipids in MTCH2 knockout cells. Importantly, MTCH2 knockout cells showed an increase in mitochondrial oxidative function, which may explain the higher energy demand. Interestingly, this imbalance in energy metabolism and reductive potential triggered by MTCH2-deletion prevents NIH3T3L1 preadipocytes from differentiating into mature adipocytes, an energy consuming reductive biosynthetic process. In summary, the loss of MTCH2 leads to increased mitochondrial oxidative activity and energy demand, creating a catabolic and oxidative environment that fails to fuel the anabolic processes required for lipid accumulation and adipocyte differentiation.PMID:39753955 | DOI:10.1038/s44318-024-00335-7

Sci Rep. 2025 Jan 3;15(1):632. doi: 10.1038/s41598-024-84840-z.ABSTRACTEndophytes are microorganisms residing in plant tissues without causing harm and their relevance in medicinal plants has grown due to their biomolecules used in pharmaceuticals. This study isolated two endophytic bacterial strains from the leaves of M. oleifera and P. betel collected from Junagadh Agricultural University. The isolates were characterized morphologically and physio-biochemically, confirming them as gram-positive or gram-negative rods and cocci. Identification using 16S rRNA gene sequencing identified isolates belonging to various genera, including Priestia aryabhattai and Kocuria rhizophila The SEM characterization of the five selected isolates revealed diverse morphological structures, including coccus and rod shapes, organized in various formations. Isolates varied in size, with N3 (Kocuria rhizophila) cocci and S5 (Priestia aryabhattai) rods. Metabolomic analysis using GC/MS and LC-MS revealed diverse metabolic profiles with key compounds like n-Hexadecanoic acid, Pyrrolo[1,2-a]pyrazine-1,4-dione, Dihydrocapsaicin, and β-Homoproline, highlighting the potential of these endophytic bacteria in agricultural applications due to their roles in membrane integrity, antioxidant properties, stress response, and antibacterial activity.PMID:39753876 | DOI:10.1038/s41598-024-84840-z

J Proteome Res. 2025 Jan 3. doi: 10.1021/acs.jproteome.4c00914. Online ahead of print.ABSTRACTMALDI-HiPLEX-IHC mass spectrometry imaging (MSI) represents a newly established workflow to map tens of antibodies linked to photocleavable mass tags (PC-MTs), which report the distribution of antigens in formalin-fixed paraffin-embedded (FFPE) tissue sections. While this highly multiplexed approach has previously been integrated with untargeted methods, the possibility of mapping target cell antigens and performing bottom-up spatial proteomics on the same tissue section has yet to be explored. This proof-of-concept study presents a novel workflow combining MALDI-HiPLEX-IHC with untargeted spatial proteomics to analyze a single FFPE tissue section, using clinical clear cell renal cell carcinoma (ccRCC) tissue as a model. Workflow implementation highlighted the need for an additional antigen retrieval step following antibody staining to aid antibody detachment and enhance tryptic digestion. Moreover, this approach enabled the stratification of histologically similar tumor cores of the same grade based on varying lymphocyte populations, particularly T regulatory cells. Finally, integration with untargeted spatial proteomics revealed proteomic alterations associated with these lymphocyte infiltration patterns. These findings demonstrate the potential of this workflow to map and characterize the molecular environment of tumor-infiltrating lymphocytes, offering insights into the molecular impact of immune cells within the tumor microenvironment.PMID:39753523 | DOI:10.1021/acs.jproteome.4c00914

Mol Oncol. 2025 Jan 3. doi: 10.1002/1878-0261.13791. Online ahead of print.ABSTRACTColorectal cancer (CRC) is a prevalent malignant tumor worldwide, with a high mortality rate due to its complex etiology and limited early screening techniques. This study aimed to identify potential biomarkers for early detection of CRC utilizing targeted metabolite profiling of platelet-rich plasma (PRP). Based on multiple reaction monitoring (MRM) mode, liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis identified metabolites in PRP collected from patients with CRC (n = 70) and healthy controls (n = 30). A total of 302 metabolites were identified and quantified in this study, including various categories such as lipids, lipid mediators, amino acids, and derivatives, organic acids and derivatives, nucleotides and derivatives, alkaloids, carbohydrates, vitamins and derivatives, and others. The differential analysis revealed that five carbohydrates and organic acids (lactose, glycerol-3-phosphate, 2-hydroxyglutaric acid, isocitric acid, and citric acid) involved in the carbohydrate metabolism pathway displayed consistent upregulation within PRP derived from patients with CRC. To further validate the abundance of differential metabolites, 10 pairs of CRC tissues, adjacent tissues, and matched PRP were collected. Ultimately, five carbohydrate metabolites were validated in PRP, and compared with carcinoembryonic antigen (CEA) and cancer antigen 19-9 (CA199), the five carbohydrate metabolites significantly improved the specificity of differentiating patients with CRC from healthy controls. Furthermore, the diagnostic efficacy of the combined five-carbohydrate metabolite panel was superior to that of individual metabolites, CEA and CA199. The sensitivity, specificity, and AUC of the metabolite panel in distinguishing patients with CRC from healthy controls were 90.00%, 96.67%, and 0.961 (95% CI 0.922-0.998), respectively. Collectively, metabolomics was used to identify and validate differential metabolites in the PRP of CRC, which may serve as potential early screening markers for patients with CRC.PMID:39753208 | DOI:10.1002/1878-0261.13791

J Hazard Mater. 2024 Dec 27;486:137024. doi: 10.1016/j.jhazmat.2024.137024. Online ahead of print.ABSTRACTPerfluorooctanoic acid (PFOA), an anthropogenic organic pollutant known for its persistence, resistance to degradation, and toxicity, has raised significant concerns about its potential ecological impacts. Zostera marina, a common submerged seagrass species in temperate offshore areas, is highly vulnerable to pollutant stressors. However, the impact of PFOA on Z. marina remains unclear. In this study, Z. marina was exposed to different concentrations of PFOA (0, 0.5, 1, 5, 10, and 20 μg/L) for 14 days. We subsequently assessed survival rates, growth patterns, physiological indices, transcriptomic profiles, and metabolomic characteristics. The results revealed dose-dependent PFOA accumulation in Z. marina tissues and significant growth inhibition. Furthermore, exposure to PFOA resulted in a significant reduction in photosynthetic pigment content (IBRv2 indices: 2.78-10.29) and elevated enzyme activity (IBRv2 indices: 2.90-8.96). Transcriptomic analysis identified 1511 differentially expressed genes associated with 11 KEGG pathways predominantly affected by PFOA exposure. Weighted gene co-expression network analysis highlighted the crucial role of the hydroxyphenylpyruvate reductase (hppr) gene in antioxidant defense mechanisms and detoxification processes against PFOA-induced stress. Metabolomics identified 412 differentially expressed metabolites, mainly consisting of flavonoids, organic acids, and lipids. In summary, PFOA exposure resulted in the down-regulation of gene expression related to photosynthesis and energy metabolism while also affecting metabolite synthesis. The response of Z. marina to PFOA stress involves modulation of the cytoskeletal dynamics and signal transduction pathways, as well as activation of a suite of genes and metabolites to initiate defense mechanisms.PMID:39752826 | DOI:10.1016/j.jhazmat.2024.137024

Microbiol Res. 2024 Dec 26;292:128038. doi: 10.1016/j.micres.2024.128038. Online ahead of print.ABSTRACTThis review addresses the significant advancements in the identification of blood-based prognostic biomarkers for tuberculosis (TB), highlighting the importance of early detection to prevent disease progression. The manuscript discusses various biomarker categories, including transcriptomic, proteomic, metabolomic, immune cell-based, cytokine-based, and antibody response-based markers, emphasizing their potential in predicting TB incidence. Despite promising results, practical application is hindered by high costs, technical complexities, and the need for extensive validation across diverse populations. Transcriptomic biomarkers, such as the Risk16 signature, show high sensitivity and specificity, while proteomic and metabolic markers provide insights into protein-level changes and biochemical alterations linked to TB. Immune cell and cytokine markers offer real-time data on the body's response to infection. The manuscript also explores the role of single-nucleotide polymorphisms in TB susceptibility and the challenges of implementing novel RNA signatures as point-of-care tests in low-resource settings. The review concludes that, while significant progress has been made, further research and development are necessary to refine these biomarkers, improve their practical application, and achieve the World Health Organization's TB elimination goals.PMID:39752806 | DOI:10.1016/j.micres.2024.128038

Int Immunopharmacol. 2025 Jan 2;147:113937. doi: 10.1016/j.intimp.2024.113937. Online ahead of print.ABSTRACTTirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors and is a promising therapeutic option for type 2 diabetes mellitus (T2DM). Nevertheless, its effect and underlying mechanism on hepatic steatosis remain ambiguous. Herein, we explored the impact of tirzepatide on improving hepatic steatosis in diabetic mice, with a particular focus on the gut microbiota and bile acids (BAs) using animal models. The tirzepatide effectively reduced body weight, improved insulin resistance, decreased serum and hepatic lipid levels, and mitigated liver injury. Compared to semaglutide, tirzepatide exhibited superior efficacy in reducing hepatic lipid accumulation. 16S rRNA gene sequencing and targeted metabolomics of BAs revealed that tirzepatide ameliorated gut microbiota dysbiosis and BAs metabolism in diabetic mice. Notably, tirzepatide observably increased the abundance of beneficial genera such as Akkermansia, elevated the ratio of farnesoid X receptor (FXR) antagonists (glycoursodeoxycholic acid: GUDCA, β-muricholic acid: β-MCA, hyodeoxycholic acid: HDCA, ursodeoxycholic acid: UDCA) to natural agonists (cholic acid: CA, lithocholic acid: LCA, chenodeoxycholic acid: CDCA, glycocholic acid: GCA, taurodeoxycholic acid: TDCA), and reduced FXR expression in intestinal tissues. In conclusion, tirzepatide attenuated hepatic steatosis in diabetic mice and regulated the gut microbiota and BAs metabolism, which may help to provide a novel therapeutic approach and therapeutic target for metabolic dysfunction-associated steatotic liver disease (MASLD).PMID:39752752 | DOI:10.1016/j.intimp.2024.113937

Food Chem. 2024 Dec 27;470:142688. doi: 10.1016/j.foodchem.2024.142688. Online ahead of print.ABSTRACTFusarium sambucinum causes dry rot disease and postharvest storage losses in potatoes. Understanding the defense mechanisms of potato plants may lead to the development of rational disease control approaches. In the present study, "Kexin one" potato variety was infected with F. sambucinum, and samples were collected at 0, 10, and 20 d post-infection and analyzed using ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry to determine metabolic differences. We identified 1049 significant differential metabolites belonging to 12 categories, including organic and amino acids and peptides, which can be biomarkers for dry rot in potatoes following F. sambucinum infection. Physiological and biochemical indicators of dry rot potatoes were explored, and the results were consistent with those of metabolomic data. The findings of this study provide a basis for the control of dry rot and prevention of postharvest losses in potatoes.PMID:39752748 | DOI:10.1016/j.foodchem.2024.142688

PLoS One. 2025 Jan 3;20(1):e0313592. doi: 10.1371/journal.pone.0313592. eCollection 2025.ABSTRACTOne way to treat diabetes mellitus type II is by using α-glucosidase inhibitor, that will slow down the postprandial glucose intake. Metabolomics analysis of Artabotrys sumatranus leaf extract was used in this research to predict the active compounds as α-glucosidase inhibitors from this extract. Both multivariate statistical analysis and machine learning approaches were used to improve the confidence of the predictions. After performance comparisons with other machine learning methods, random forest was chosen to make predictive model for the activity of the extract samples. Feature importance analysis (using random feature permutation and Shapley score calculation) was used to identify the predicted active compound as the important features that influenced the activity prediction of the extract samples. The combined analysis of multivariate statistical analysis and machine learning predicted 9 active compounds, where 6 of them were identified as mangiferin, neomangiferin, norisocorydine, apigenin-7-O-galactopyranoside, lirioferine, and 15,16-dihydrotanshinone I. The activities of norisocorydine, apigenin-7-O-galactopyranoside, and lirioferine as α-glucosidase inhibitors have not yet reported before. Molecular docking simulation, both to 3A4A (α-glucosidase enzyme from Saccharomyces cerevisiae, usually used in bioassay test) and 3TOP (a part of α-glucosidase enzyme in human gut) showed strong to very strong binding of the identified predicted active compounds to both receptors, with exception of neomangiferin which only showed strong binding to 3TOP receptor. Isolation based on bioassay guided fractionation further verified the metabolomics prediction by succeeding to isolate mangiferin from the extract, which showed strong α-glucosidase activity when subjected to bioassay test. The correlation analysis also showed a possibility of 3 groups in the predicted active compounds, which might be related to the biosynthesis pathway (need further research for verification). Another result from correlation analysis was that in general the α-glucosidase inhibition activity in the extract had strong correlation to antioxidant activity, which was also reflected in the predicted active compounds. Only one predicted compound had very low positive correlation to antioxidant activity.PMID:39752479 | DOI:10.1371/journal.pone.0313592

Alzheimers Dement. 2024 Dec;20 Suppl 1:e092897. doi: 10.1002/alz.092897.ABSTRACTBACKGROUND: Microglial processing and recycling of debris is implicated in AD. AD GWAS loci are enriched for genes in efferocytosis, phagocytosis, endosomal trafficking and cholesterol efflux. Acting as a buffer, lipid droplets increase as a consequence of an imbalance between lipid debris influx and efflux rates. We hypothesize that a pivotal point in disease progression occurs when this buffering saturates, resulting in expanded lipid-droplet accumulating microglia (LDAM). We anticipate a positive-feedback effect where saturation accelerates neurodegeneration via inflammation and lipid processing via astrocytes. Susceptibility to this saturation may be connected to microglial AD GWAS loci-and would be reflected in progression rates. To explore this hypothesis, we analyzed lipidomic, proteomic, cognitive and genetic ADNI data to identify a signature indicative of this inflection point.METHOD: We identified ADNI individuals in comparable states of disease progression, grouping them into ADAS13 (cognitive score) quartiles, then examined blood lipidomic and CSF proteomic data. This resulted in a cross-sectional dataset of 608 subjects spanning from cognitively normal to demented. We examined protein/lipid correlations across each quartile, identifying and characterizing inflection points.RESULT: We observed a stark and unique pattern of correlations in individuals with an ADAS13 score range from 13 to 19. We observed two subpopulations that differed in their rate of disease progression. CSF proteins in the rapid progressors point to microglial lipid droplet signaling and the lactate shuttle. We observed key changes in plasmalogens and cholesterol esters with DHA fatty acid tails, both indicative of neuronal debris processing and reverse cholesterol transport, as well as changes in acylcarnitines-indicative of reduced lipid hydrolysis. We also found differential enrichment of specific AD GWAS loci between the fast and slow progressors.CONCLUSION: Our analysis provides evidence for the importance of lipid droplet saturation coinciding with correlational changes in CSF proteins and plasma lipids, occurring in individuals transitioning from cognitively normal to MCI. We connected microglial AD GWAS loci to differences in the progression rates at this transition. These results have potential clinical relevance for predicting progression rate at MCI diagnosis, and inform our understanding of the role of GWAS loci in key transitions.PMID:39750930 | DOI:10.1002/alz.092897

Aging Dis. 2024 Dec 10. doi: 10.14336/AD.2024.1298. Online ahead of print.ABSTRACTAngina pectoris (AP), a clinical syndrome characterized by paroxysmal chest pain, is caused by insufficient blood supply to the coronary arteries and sudden temporary myocardial ischemia and hypoxia. Long-term AP typically induces other cardiovascular events, including myocardial infarction and heart failure, posing a serious threat to patient safety. However, AP's complex pathological mechanisms and developmental processes introduce significant challenges in the rapid diagnosis and accurate treatment of its different subtypes, including stable angina pectoris (SAP), unstable angina pectoris (UAP), and variant angina pectoris (VAP). Omics research has contributed significantly to revealing the pathological mechanisms of various diseases with the rapid development of high-throughput sequencing approaches. The application of multi-omics approaches effectively interprets systematic information on diseases from the perspective of genes, RNAs, proteins, and metabolites. Integrating multi-omics research introduces novel avenues for identifying biomarkers to distinguish different AP subtypes. This study reviewed articles related to multi-omics and AP to elaborate on the research progress in multi-omics approaches (including genomics, transcriptomics, proteomics, and metabolomics), summarized their applications in screening biomarkers employed to discriminate multiple AP subtypes, and delineated integration methods for multi-omics approaches. Finally, we discussed the advantages and disadvantages of applying a single-omics approach in distinguishing diverse AP subtypes. Our review demonstrated that the integration of multi-omics technologies is preferable for quick and precise diagnosis of the three AP types, namely SAP, UAP, and VAP.PMID:39751862 | DOI:10.14336/AD.2024.1298

Alzheimers Dement. 2024 Dec;20 Suppl 1:e085269. doi: 10.1002/alz.085269.ABSTRACTBACKGROUND: The recent European-ancestry based genome-wide association study (GWAS) of Alzheimer disease (AD) by Bellenguez2022 has identified 75 significant genetic loci, but only a few have been functionally mapped to effector gene level. Besides the large-scale RNA expression, protein and metabolite levels are key molecular traits bridging the genetic variants to AD risk, and thus we decided to integrate them into the genetic analysis to pinpoint key proteins and metabolites underlying AD etiology. Few studies have generated more than one layer of post-transcriptional phenotypes, limiting the scale of biological translation of disease modifying treatments.METHODS: We first performed the plasma proteomic (6,907 proteins by SomaScan) and metabolomic (1,483 metabolites by Metabolon) GWAS from the same participants of European (N = 2,300) ancestry. Using these significant variant-trait associations, we next performed multiple post-GWAS analyses (functional summary-based imputation (FUSION) and genetic colocalization) to identify the AD associated proteins and metabolites. To annotate these findings with brain aging clocks predicated from the plasma proteomics data, we performed association tests between the aging gaps with the molecular phenotypes.RESULTS: We identified hundreds to thousands of QTLs (quantitative trait loci). In the proteomic GWAS, we found 2,400 proteins with 2,848 study-wide significant pQTLs. In the metabolomic GWAS, we reported 403 metabolites with 490 study-wide significant mQTLs. In total, 86% and 98% of these associations have supported by the previous larger-scale plasma-based studies in proteome and metabolome, respectively. Under the FUSION framework, we found 95 proteins were study-wide significant associated with AD risk, including, proteins TREM2, APOE, and NfL. After removing the bias of linkage disequilibrium by colocalization, we obtained a list of 53 proteins, of which 42 were not reported. On the other hand, 35 nominal significant metabolites, such as androsterone sulfate, were associated with AD in the FUSION analysis. Of these findings, eight metabolites were also highly colocalized with AD. There were 14 proteins and three metabolites significantly associated with the brain aging gaps, which included TREM2, but not APOE.CONCLUSIONS: Our study serves the first duo-omics post-transcriptional genetic study for studying AD risk effectors and can facilitate developing novel disease modifying treatments.PMID:39751800 | DOI:10.1002/alz.085269

Alzheimers Dement. 2024 Dec;20 Suppl 1:e084789. doi: 10.1002/alz.084789.ABSTRACTBACKGROUND: Host commensal gut microbes are shown to be crucial for microglial maturation, and functions that involve innate immune responses to maintain brain homeostasis. Sex has a crucial role in the incidence of neurological diseases with females showing higher progression of AD compared with males. Transcriptomics has been a powerful tool for the characterization of microglial phenotypes however, there is a large gap in relating to their functional protein abundances. Here, we generated 'APPPS1-21-CD11br' a translating ribosome affinity purification (TRAP) mice model and assessed the influence of gut microbiome on microglial protein networks during their phenotypic transition in a sex-specific manner.METHODS: APPPS1-21 mice were crossed with WT-CD11br mice wherein a CD11b-promoter drives expression of ribosomal protein L10a (RpL10) that is fused to FLAG/EGFP at the amino-terminus to generate APPPS1-21-CD11br transgenic mice. Six groups of mice that included WT-CD11br, antibiotic (ABX) or vehicle-treated APPPS1-21-CD11br male and female were sacrificed at 7-weeks of age (n = 15/group) and used for immunoprecipitation of microglial polysomes from cortical homogenates using anti-FLAG antibody. Liquid chromatography coupled to tandem-mass-spectrometry (LC-MSMS) and label-free quantification was used to identify newly synthesized peptides extracted from polysomes.RESULTS: Proteomic analysis reveal that Aβ-induced microglial activation resulted in increased FcgR-mediated-phagocytosis and actin organization in male and female AD mice respectively. ABX-treatment resulted in substantial remodeling of epigenetic landscape, leading to a metabolic shift that accommodates the increased bioenergetic and biosynthetic demands associated with microglial polarization in a sex-specific manner. While microglia in ABX-treated male mice exhibited a metabolic shift towards ketogenesis to promote neuroprotective phenotype mediating lysosomal Aβ clearance, microglia in ABX-treated female mice exhibited persistent mitochondrial dysfunction and impaired clearance associated with inflammatory phenotypes. Targeted metabolomics show sex-specific changes in immunomodulatory gut metabolites mediated by ABX-treatment.CONCLUSIONS: Our studies provide first snapshot of dynamic translational state of microglia in cerebral Aβ-amyloidosis models with an altered gut-microbiome. Gut metabolites can support microglial metabolic plasticity to modulate immune responses and amyloid clearance in a sex-specific manner. Reprogramming of microglial metabolism could be a promising strategy for restoring their physiological functions in a manner that might halt the progression of AD.PMID:39751737 | DOI:10.1002/alz.084789

Geroscience. 2025 Jan 3. doi: 10.1007/s11357-024-01478-5. Online ahead of print.ABSTRACTUsing whole-genome sequencing (WGS) might offer insights into rare genetic variants associated with healthy aging and extreme longevity (EL), potentially pointing to useful therapeutic targets. In this study, we conducted a genome-wide association study using WGS data from the Long Life Family Study and identified a novel longevity-associated variant rs6543176 in the SLC9A2 gene. This SNP also showed a significant association with reduced hypertension risk and an increased, though not statistically significant, cancer risk. The association with cancer risk was replicated in the UK Biobank and FinnGen. Metabolomic analyses linked the rs6543176 longevity allele to higher serine levels, potentially associated with delayed mortality. Our findings warrant further investigation of SLC9A2's role in both longevity and cancer susceptibility, and they highlight the need for careful evaluation in developing anti-aging therapies based on EL-associated alleles.PMID:39751714 | DOI:10.1007/s11357-024-01478-5

Alzheimers Dement. 2024 Dec;20 Suppl 1:e091089. doi: 10.1002/alz.091089.ABSTRACTBACKGROUND: The Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) is a public-private partnership linking NIH, the FDA, pharmaceutical companies, and nonprofit organizations in an interactive, collaborative program utilizing transcriptomics, genomics, metagenomics, proteomics, and metabolomics to provide data for computational analysis, that, in turn, enables promising targets to be ranked by a combination of omic scores and druggability. This ranking informs the selection of targets for validation.METHOD: Human postmortem samples were obtained from Mount Sinai, ROSMAP (Religious Orders Study and Rush Memory and Aging Project), Mayo Clinic (Florida), and Columbia University. The validation systems were mouse and fly models of AD pathology and human induced pluripotent stem cells (hiPSCs). Target genes were up- or down- regulated or mutated to determine whether AD-related phenotypes were altered.RESULT: Targets selected for validation by AMP-AD included genes expressed in neurons (e.g., VGF, REST, ATP6V1A), microglia (e.g., BIN1, TYROBP, TREM2, SYK, MSN, INPP5D), or astrocytes (e.g., PLEXNB1, GJA1). As expected, phenotypes were improved by decreasing levels of proteins that are abnormally elevated in AD or by increasing the levels of proteins that are abnormally decreased in AD. Qualitative and quantitative variability in effects of target manipulation may be attributable to duration or stage of disease at the time of intervention, and/or to the cell type that expresses each target. AD-related changes were used to predict therapeutic directionality, but up- and down-regulation sometimes had similar effects. Plaque load changes did not reliably predict changes in other aspects of the phenotype. Paradoxically, manipulation of some targets (e.g., ABI3) caused amyloidosis and tauopathy to change in different directions.CONCLUSION: Validation experiments in multiple systems support the AMP-AD approach for selecting druggable targets for the treatment of AD. Future work will focus on validation of additional targets and close collaboration with the Target Enablement to Accelerate Therapy in AD (TREAT-AD) Consortium to develop pharmacologic agents derived from these discoveries.PMID:39751603 | DOI:10.1002/alz.091089

Alzheimers Dement. 2024 Dec;20 Suppl 1:e089824. doi: 10.1002/alz.089824.ABSTRACTBACKGROUND: Agora (https://agora.adknowledgeportal.org) is an openly available web resource developed to enable a broad spectrum of Alzheimer's disease (AD) researchers access to target-based evidence generated within the translational research portfolio of the National Institute on Aging (NIA). Agora aims to accelerate AD research and maximize therapeutic discovery by sharing information using interactive tools, data visualizations, and summarized evidence.METHOD: Agora enables the sharing of information about potential AD therapeutic targets by surfacing data visualizations, summary evidence, and results from targeted validation studies. Agora users can browse a list of over 950 potential therapeutic targets that have been nominated by the NIA's Accelerating Medicines Partnership in AD (AMP-AD) consortium and Target Enablement to Accelerate Therapy Development for AD (TREAT-AD) centers, and by the broader AD research community; see visualizations and summarized information based on harmonized genome-wide analyses of high-dimensional human transcriptomic, proteomic, and metabolomic data; use interactive tools designed to enable non-bioinformaticians to evaluate and compare complex multi-omic data; and access the underlying data that drives the results and visualizations presented in the application.RESULT: Agora presents information and results about AD targets using approaches that make this information accessible to a broad spectrum of AD researchers. Recent updates to Agora include 1) comparative and per-target visualizations for SRM proteomic differential expression results and 2) enabling the discovery of TREAT-AD Target Experimental Resources for supported targets.CONCLUSION: The advancement of promising new AD therapeutics requires efforts from research groups and specialties across both academia and industry. Agora enables the AD research community to develop and share target hypotheses that will accelerate the investigation of promising new AD therapeutic targets, pathways and mechanisms.PMID:39751588 | DOI:10.1002/alz.089824

Alzheimers Dement. 2024 Dec;20 Suppl 1:e089796. doi: 10.1002/alz.089796.ABSTRACTBACKGROUND: Alzheimer's disease (AD) risk and progression are significantly influenced by ApoE genotypes, with ApoE4 increasing and ApoE2 decreasing the susceptibility compared to ApoE3. Understanding metabolic pathways affected by ApoE genotypes will help decipher disease development and identify new therapeutic targets.METHOD: This study investigates the impact of ApoE genotypes on aging brain metabolic trajectories using human ApoE-targeted replacement mice. Applying Biocrates P180 targeted metabolomics platform, we analyzed the metabolic impact of ApoE2/2, ApoE3/3, and ApoE4/4 on fatty acid β-oxidation, amino acids, and phospholipids, which are known to be altered in AD. Furthermore, we compared our rodent model results with human dorsolateral prefrontal cortex data from the Religious Orders Study/Memory and Aging Project (ROS-MAP).RESULT: We found aging mice carrying ApoE2/2 had altered branch-chain amino acid metabolism and increased C5 acylcarnitine and its ratio to precursor isoleucine, pointing towards increased β-oxidation and branched-chain amino acid (BCAA) utilization. Furthermore, ROS-MAP data revealed the ApoE2 genotype affects similar areas of metabolism in humans. Additionally, our data provide comprehensive insight into age-related metabolic changes of the current mice model, independent of ApoE genotype, among phospholipids, sphingomyelins, amino acids, and biogenic amines. Many of the observed differences are also known aging markers in humans, with a connection to cognition and Alzheimer's disease.CONCLUSION: Together, these results suggest a potential involvement of ApoE2/2 genotype in energy metabolism and characterize the current mice model for further study of ApoE in AD, brain aging, and brain BCAA utilization for energy.PMID:39751556 | DOI:10.1002/alz.089796

Alzheimers Dement. 2024 Dec;20 Suppl 1:e089802. doi: 10.1002/alz.089802.ABSTRACTBACKGROUND: Peripheral metabolic health status can reflect and/or contribute to the risk of Alzheimer's disease (AD). Peripheral metabolic health status can be indicated by metabolic health markers, such as inflammatory biomarker glycoprotein acetyls (GlycA) and specific components of lipoproteins (e.g., triacylglycerol of high-density lipoprotein). However, it is unclear if the relationship between peripheral metabolism and AD-related markers is heterogenous among diverse populations and throughout the disease progression.METHODS: Utilizing Alzheimer's Disease Neuroimaging Initiative data, we determined whether baseline plasma GlycA can inform on cognitive and brain structural changes among sub-populations with different diagnosis status. Furthermore, correlation analyses were performed between blood metabolomics and cerebrospinal fluid (CSF) proteomics data in sub-populations with different diagnosis status or different mild cognitive impairment (MCI)/AD outcomes in 3 years.RESULTS: GlycA was elevated in AD patients compared to cognitively normal participants. Baseline GlycA level was associated with executive function decline at 3-9 year follow-up in participants diagnosed with late mild cognitive impairment (LMCI) at baseline, with similar but not identical trends observed in the future decline of memory and entorhinal cortex volume. In addition, peripheral metabolomics signatures of CSF proteomics were well-distinguished between cognitive normal participants and AD patients. Moreover, different peripheral-central metabolic connection was also observed in MCI-AD converters vs. MCI-MCI non-converters across 3 years follow up.CONCLUSION: Peripheral inflammation was linked to future cognitive decline and brain structural atrophy for population at risk. In addition, peripheral metabolomics-CSF proteomics correlation reveals distinguishing peripheral-central connection patterns in AD patients as well as MCI participant soon to develop AD in 3 years. Findings here point to peripheral systemic inflammation and metabolic health in general as risk factors in AD development, pointing to therapeutic intervention related to periphery metabolic health for patients at risk.PMID:39751544 | DOI:10.1002/alz.089802

Alzheimers Dement. 2024 Dec;20 Suppl 1:e091247. doi: 10.1002/alz.091247.ABSTRACTBACKGROUND: Compared with the E3 allele of Apolipoprotein E (APOE), E4 increases late-onset Alzheimer's Disease (AD) risk up to 15-fold, while the E2 allele substantially decreases risk. In the CNS, ApoE is predominantly synthesized by astrocytes and microglia, making these two cell types promising targets for ApoE-directed therapeutic approaches. Our lab has generated an inducible "switch" mouse model (APOE4s2) in which we can conditionally replace E4 with the protective E2 in a cell-specific manner. To elucidate potential mechanisms by which astrocytes and microglia expressing E2 or E4may modulate AD risk, we characterized the immuno-metabolic response of astrocyte- and microglia-specific "switch" mice to a variety of CNS-related challenges.METHOD: Aged APOE4s2 mice were administered tamoxifen to induce an in vivo transition from expression of E4 to E2 selectively in astrocytes (Aldh1l1-CreERT2) or microglia (Tmem119-CreERT2). A separate cohort of APOE4s2 mice received LPS to induce an inflammatory response 24 hours prior to tissue collection. Immunohistochemical analysis of gliosis (GFAP, IBA1), cytokine measurements, and targeted metabolomics and lipidomics were performed on brain tissue from these groups. Additionally, a cohort of 6-week-old microglia-APOE4s2 mice were administered lysophosphatidylcholine (LPC) via intracranial injections to promote demyelination. Mice were sacrificed 10 days post-LPC injection, and myelin content and glial reactivity were quantified via staining of myelin basic protein (MBP), degraded MBP (dMBP), and Luxol Fast Blue (LFB).RESULT: As measured by plasma and brain cytokine levels, the inflammatory response was not modified by glial E2 expression in either age or LPS. However, aged E4 mice in which only astrocytes selectively expressed E2 showed decreased microglia reactivity (Iba1 immunoreactivity) compared to mice expressing E4 in all cell types. In contrast, aged mice in which only the microglia express E2 showed increased microglia reactivity relative to E4 expressing controls. Interestingly, a similar increase in Iba1 signal was noted in mice expressing only astrocytic E2 following an acute exposure to LPS. Finally, E2 expressing microglia appear to have higher levels of myelin following LPC injections compared to E4 expressing microglia.CONCLUSION: Glial cell-specific expression of E2 alters microglia reactivity in response to various pathological challenges, including aging, inflammatory stimuli, and demyelination.PMID:39751498 | DOI:10.1002/alz.091247

Alzheimers Dement. 2024 Dec;20 Suppl 1:e086331. doi: 10.1002/alz.086331.ABSTRACTBACKGROUND: Despite recent breakthroughs, Alzheimer's disease (AD) remains untreatable. In addition, we are still lacking robust biomarkers for early diagnosis and promising novel targets for therapeutic intervention. To enable utilizing the entirety of molecular evidence in the discovery and prioritization of potential novel biomarkers and targets, we have developed the AD Atlas, a network-based multi-omics data integration platform. Through recent extensions, the AD Atlas provides a comprehensive database of high-quality multi-omics data that can be utilized for hypothesis-free ranking of molecular markers and disease modules, as well as prioritization of potential novel targets and drug repositioning candidates.METHOD: We developed several graph-based analysis tools from proximity searches to applications of artificial intelligence that can be applied to the AD Atlas. For prioritization of potential targets and biomarkers, we derived several network-based metrics to score -omics entities for disease relevance by not only assessing evidence for a single marker but also for its functional neighborhood in the AD Atlas network. For disease module identification, we employed graph representation learning coupled with unsupervised clustering to extract functional modules as defined by the network structure. Finally, we propose an ensemble approach that enables weighted aggregation of drug repositioning predictions from both signature-based and network-based algorithms.RESULT: We demonstrate that the AD Atlas enables complex computational analyses for target and biomarker discovery and prioritization as well as in silico drug repositioning in AD. Using the integrated scores for prioritizing single targets and biomarkers for AD, we observe significantly higher relevance scores for genes that have been nominated as promising targets by the AMP-AD consortium. We further find that extracted disease modules are enriched for specific AD-relevant biological domains and can be ranked by disease relevance using similar graph-based metrics. Finally, we demonstrate that drug repositioning candidates are significantly enriched for compounds that were or are being tested in clinical trials for AD.CONCLUSION: High-quality, multi-omics networks, such as the AD Atlas, enable exploitation of large-scale heterogeneous data through computational applications for target, biomarker, disease module, and drug repositioning candidate discovery and prioritization.PMID:39751427 | DOI:10.1002/alz.086331