PubMed

Alzheimers Dement. 2024 Dec;20 Suppl 1:e092564. doi: 10.1002/alz.092564.ABSTRACTBACKGROUND: Alzheimer's disease (AD) is the most common type of dementia which results in debilitating memory loss as the disease advances. However, among older adults with AD, some may experience rapid cognitive decline while others may maintain a stable cognitive status for years. In addition to the amyloid plaques, tau tangles, and neuronal inflammation characteristic of AD, there is strong evidence of dysregulation in the peripheral immune system, including decreased naïve T cells and increased memory T cells among older adults with AD. It is currently unknown what underlies dysfunction in the peripheral immune system or whether changes in peripheral immune cells are associated with cognitive decline.METHOD: We have performed unbiased metabolomics and characterized stool metabolites present in 35 AD versus 35 propensity matched healthy controls. In our ongoing work, we are longitudinally characterizing resting peripheral immune cell populations by flow cytometry and gut microbiome composition by metagenomic sequencing.RESULT: We have identified an increase in the metabolites methionine sulfone (1.46 fold, p<0.05), homocysteine (1.67 fold, p<0.05), and cysteine (1.33 fold, p<0.05) in the stool of older adults with AD compared to controls. Among the population of AD patients experiencing cognitive decline, determined by increasing ADAS-Cog score >6 points over one year (n = 7 declining vs n = 8 stable cognition), we have identified increases in the bacterial genes responsible for methionine production at the point of cognitive decline compared to previous timepoints and between patients with decline versus stable cognition. In accordance with the role of methionine in promoting immune cell proliferation and differentiation, we have compared the composition of peripheral immune cells among adults with declining versus stable cognition and identified a decrease in CD4+/CD62L+ naïve T cells (percent of CD4+ lymphocytes, stable 0.3055 vs declining 0.0955, p = 0.0042) and increased effector memory CD4+ T cells (percent of CD4+ lymphocytes, stable = 0.2375 vs declining = 0.4164, p = 0.0225).CONCLUSION: This longitudinal clinical study identifies changes in stool metabolites and resting peripheral T cell populations in AD patients and among AD patients with cognitive decline. We propose that gut bacterial produced methionine acts to promote peripheral immune differentiation and dysfunction, leading to cognitive decline in AD.PMID:39751320 | DOI:10.1002/alz.092564

Alzheimers Dement. 2024 Dec;20 Suppl 1:e085147. doi: 10.1002/alz.085147.ABSTRACTBACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia worldwide. Dysregulation of various metabolism pathways may mediate the development of AD pathology and cognitive dysfunction. Variants of triggering receptor expressed on myeloid cells-2 (TREM2) are known to increase the risk of developing AD. TREM2 plays a role in AD development by maintaining cellular energy and biosynthesis, but the precise mechanism through which it accomplishes this is unknown.METHOD: In the present study, we explored whether TREM2 plays a role in AD development by maintaining cellular energy and biosynthesis with the help of an AD mouse model (APP/PS1). First, we performed untargeted metabolomics analysis of hippocampal tissues from APP/PS1 transgenic AD mice (APP/PS1-TREM2 KO mice) and APP/PS1 transgenic AD mice (APP/PS1 mice), which revealed the changes of different metabolites after TREM2 knockdown. Next, we performed transcriptomic analysis to identify differentially expressed genes (DEGs). Finally, we used metabolomics and transcriptomics analysis to screen for genes associated with lipid metabolism.RESULT: Metabolomic analysis of hippocampal tissue from APP/PS1 and APP/PS1-TREM2 knockout (KO) mice found that TREM2 KO was associated with abnormalities in several metabolism pathways, and the effect was particularly pronounced in lipid metabolism and glucose metabolism pathways. Consistently, transcriptomic analysis of these mice determined that most differentially expressed genes were involved in energy metabolism pathways. We screened seven differentially expressed genes in APP/PS1-TREM2 KO mice that may influence AD development by altering energy metabolism. Integrative analysis of the metabolomic and transcriptomic profiles showed that TREM2 may regulate lipid metabolism and sphingolipid metabolism by affecting lipoprotein lipase (LPL) expression, thereby influencing AD progression.CONCLUSION: TREM2 knockout was found to be associated with abnormalities in multiple metabolic pathways in AD mice, particularly lipid metabolism and glucose metabolism. Also, LPL is a novel gene that may affect lipid metabolism and sphingolipid metabolism in AD mice.PMID:39751228 | DOI:10.1002/alz.085147

Alzheimers Dement. 2024 Dec;20 Suppl 1:e089489. doi: 10.1002/alz.089489.ABSTRACTBACKGROUND: The Apolipoprotein-E (APOE) ε4 gene variant is the strongest genetic risk factor for late-onset Alzheimer's Disease, but is not entirely predictive. Emerging evidence suggests environmental factors contribute to disease etiology, with epidemiological studies associating pesticide exposure with lower cognitive scores. Dichlorodiphenyltrichloroethane (DDT), a pesticide used extensively in the US until 1972, persists in trace amounts due to its long half-life, bioaccumulation, and existing dumpsites. We have previously reported that DDT induces AD pathology in multiple models and also shown increased serum levels of DDE, the primary metabolite of DDT, in AD patients, where APOE genotype modified MMSE scores and contributed a ∼4-fold increase in AD risk. Here, we sought to identify the mechanism(s) by which APOE4 genotype alters pathological response to DDT by a multi-omics approach.METHOD: To assess the effects of DDT exposure, three-month-old male and female APOE3 (E3) and APOE4 (E4) mice were exposed to 3 mg/kg DDT by oral gavage every 3 days for 5 months. Hippocampus was dissected out and frozen for RNA-sequencing and metabolomic analysis, while serum was collected for metabolomic analysis and biomarker measurement.RESULT: RNA-sequencing analysis between genotypes of female DDT-exposed mice indicated significantly downregulated pathways and functions (p<0.05) in the hippocampus of E4-females, including phosphatidylserine decarboxylase activity and neuron projection. Similarly, DDT-exposed E4-males indicated downregulation of ion channel regulator activity, nucleotide binding, cell-cell and synaptic signaling, and neuron projection. Further, untargeted metabolomic analysis of DDT-exposed mice was compared. Top pathways (p<0.05) altered in E4 vs. E3 female-DDT hippocampus were carnitine shuttle and glycolysis-gluconeogenesis, while serum changes included TCA cycle and tryptophan metabolism. In E4 vs. E3 male-DDT, hippocampal alterations included purine metabolism, fatty acid mitochondrial beta-oxidation, TCA cycle, glycolysis, and carnitine shuttle, while serum changes involved cholesterol biosynthesis, TCA cycle, and glycolysis-gluconeogenesis. Finally, DDT increased serum neurofilament light chain (NfL) levels, a biomarker for neurodegeneration, by 1.9 and 2.1-fold in E4-male and E4-female mice compared to respective controls. NfL was 1.4-fold higher in DDT-exposed E4-females compared to E4-males.CONCLUSION: These data demonstrate gene-by-environment interactions modified by sex, providing a platform to investigate mechanisms in AD-related neurodegeneration and corroborating previous epidemiological findings.PMID:39751129 | DOI:10.1002/alz.089489

Alzheimers Dement. 2024 Dec;20 Suppl 1:e088373. doi: 10.1002/alz.088373.ABSTRACTBACKGROUND: The GI tract is home to approximately 70% of the body's immune cells, >100 million enteric neurons, and ∼40 trillion bacteria. This co-localization of myriad immune, neural and bacterial cells creates complex interactions that regulate almost every tissue in the body, including the brain. Importantly, peripheral and GI inflammation occur in neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer (AD) contributing to gut brain axis. The activation state and function of microglia, brain-resident innate immune cells, has been implicated in AD mouse models and is regulated by the gut microbiome. Gut microbial changes are linked to development of neuropsychiatric diseases. These disorders, classically studied from a brain-centric view and associated with neuroinflammation, often exhibit GI symptoms and peripheral inflammation.METHOD: In this session we will address metabolomics technologies applied by the Alzheimer Disease Metabolomics Consortium (ADMC) for the study of Alzheimer disease. State-of-the-art metabolomics and lipidomics technologies combined with genomic and imaging data are used to map metabolic failures across the trajectory of the disease. Immune metabolomics platforms are being developed and used to link immune function changes and metabolic alterations in blood and in immune cells with link to cognition.RESULT: Our studies confirmed that peripheral metabolic changes influenced by the exposome and gut microbiome inform about cognitive changes, brain imaging changes, and ATN markers for disease confirming that peripheral and central changes are connected, in part through the metabolome. We defined metabolic differences between men and women with AD, developed initial brain metabolome for AD and defined lipidomics signatures that inform about mechanism of APOE ε2 resilience for AD. A major role for inflammation and immune dysregulation is noted and linked to signatures that inform about cognition and brain imaging changes. We will illustrate how we are applying immune metabolomics platforms to map cross talk between metabolism immune function inflammation and brain metabolic health.CONCLUSION: Metabolomics presents powerful tools to the study of inflammation, immune dysregulation, in AD pathogenesis.PMID:39751128 | DOI:10.1002/alz.088373

Alzheimers Dement. 2024 Dec;20 Suppl 1:e088847. doi: 10.1002/alz.088847.ABSTRACTBACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease and a leading cause of senile dementia. Accumulation of amyloid-β (Aβ) in the brains causes chronic neuroinflammation, synaptic loss, and neurovascular damage, which is thought to initiate decades-long AD pathogenesis. Recent clinical trials for anti-Aβ immunotherapy highlights the utility of biomarkers that faithfully reflect Aβ-related brain pathology to diagnose AD at the preclinical stage, to predict the onset and progression of the disease, and to assess the therapeutic efficacy of drugs.METHOD: To search for plasma metabolites reflecting neuroinflammation due to Aβ accumulation, we conducted untargeted metabolomics in plasma and analyzed potential roles of metabolic changes in neuroinflammatory response in brains using Appknock-in (AppNLGF) mouse model of brain parenchymal Aβ amyloidosis.RESULT: The capillary electrophoresis-time-of-flight mass spectrometry analysis on plasma samples from wild-type and AppNLGF mice revealed that plasma nicotinamide levels were significantly reduced in AppNLGF mice, and "nicotinate and nicotinamide metabolism" was the most enriched pathway of altered metabolite profiles. Nicotinamide is a precursor of nicotinamide adenine dinucleotide (NAD+). In AppNLGF mouse brains, while NAD+ levels were unaltered, mRNA levels of NAD+-synthesizing and NAD+-degrading genes were increased, and these enzymes were expressed in reactive astrocytes and microglia surrounding Aβ plaques.CONCLUSION: This study suggests that alterations in plasma nicotinamide levels may be a potential biomarker to assess neuroinflammatory response against Aβ pathology and "nicotinate and nicotinamide metabolism" may be a potential therapeutic target to prevent the onset of AD by targeting both neuroinflammation and neuroprotection.PMID:39751101 | DOI:10.1002/alz.088847

Alzheimers Dement. 2024 Dec;20 Suppl 1:e087578. doi: 10.1002/alz.087578.ABSTRACTBACKGROUND: Microglia, the innate immune cells of the brain, are a principal player in Alzheimer's Disease (AD) pathogenesis. Their surveillance of the brain leads to interaction with the protein aggregates that drive AD pathogenesis, most notably Amyloid Beta (Aβ). Aβ can elicit attempts from microglia to clear and degrade it using phagocytic machinery, spurring damaging neuroinflammation in the process. SCFAs, abundant microbial byproducts of dietary fiber fermentation, are blood-brain-barrier permeable molecules that have recently been shown to modulate microglial function. Further, as dietary manipulation can drastically alter SCFA abundances and thus modulate AD microglia, it is crucial to understand SCFAs effects. Propionate, one SCFA, is more poorly characterized than the rest, and thus we attempted to conduct a detailed characterization of propionate's impact on microglial function in an AD-relevant in vitro experiment.METHOD: Using a multi-omics approach, we characterized the transcriptomic, metabolomic, and lipidomic responses of immortalized murine microglia following 1 hour of Aβ stimulation, as well as characterizing secretion of reactive nitrogen species (RNS) in response to Aβ, using RNA sequencing, LCMS-based metabolomics, and a fluorescently coupled RNS detector, respectively.RESULT: Propionate significantly blunted the early inflammatory response driven by Aβ, driving down the expression of many Aβ-stimulated immune genes, including those regulating inflammation, the immune complement system, and chemotaxis. Further, it reduced the expression of inflammation-promoting Aβ-binding scavenger receptors such as cd36 and msr1 in favor of more neutral lpl. Finally, propionate shifted microglial metabolism, altering phospholipid composition and shunting arginine synthesis away from nitric oxide synthesis, which resulted in decreased nitric oxide production.CONCLUSION: Altogether, our data demonstrate a modulatory role of propionate on microglia that may dampen immune activation in response to Aβ and potentially improve AD pathogenesis.PMID:39751087 | DOI:10.1002/alz.087578

Alzheimers Dement. 2024 Dec;20 Suppl 1:e087508. doi: 10.1002/alz.087508.ABSTRACTBACKGROUND: At least one-third of the identified risk alleles from Genome Wide Association Studies of Alzheimer's disease (AD) are involved in lipid metabolism, lipid transport, or direct lipid binding. BIN1 which is also known as Amphiphysin 2; and PICALM which are involved in phosphoinositide metabolism and binding rank just below the highest risk gene variant of Apolipoprotein E (ApoEε4), a cholesterol and phospholipid transporter. In addition to genetic variants, lipidomic studies have reported severe metabolic dysregulation in human autopsy brain tissue, CSF, blood and multiple mouse models of AD. We aimed to identify an overarching metabolic pathway in lipid metabolism by integrating analyses of transcriptomics and lipidomics in the Religious Order Study-Memory Aging Project (ROS-MAP) as well as models of disease.METHOD: Lipidomic data in ROS-MAP was generated using the Biocrates AbsoluteIDQ p180 platform, a multiplexed targeted metabolomic assay covering lipids and metabolites including acylcarnitines, glycerophospholipids and sphingolipids. We confirmed global lipid dysregulation of acyl chain remodeling using pharmacological inhibitors of lipid modifying enzymes in cell models overexpressing amyloid precursor protein (APP) and identified similarly dysregulated lipids in an animal model of AD overexpressing APP harboring the Swedish mutation in a targeted lipidomic panel of over 600 lipid species.RESULT: Our analysis of transcriptomic data from ROS-MAP lead to identification of multiple genes in the pathway for acyl chain remolding, Lands Cycle, which were associated with cognitive decline independently of amyloid and tau pathologies. Coordinate changes in lipids were found to be dysregulated in association with both mild cognitive impairment (MCI) and the ApoEe4 genotype which showed a correlated lipid profile shift. WGCNA analysis identified dysregulated lipids within a single module which are substrates and products in the Lands Cycle for acyl chain remodeling.CONCLUSION: Our studies highlight the critical dysregulation of acyl chain remodeling in ApoEe4 carriers and MCI in human brain which could be modeled in mouse and cell models of disease. A coordinated lipid profile shift in both ApoEe4 carriers and MCI suggest pathological changes in lipid metabolism underly early disease and highlight lipid dyshomeostasis as a tractable target for early disease modifying intervention.PMID:39750999 | DOI:10.1002/alz.087508

Alzheimers Dement. 2024 Dec;20 Suppl 1:e086461. doi: 10.1002/alz.086461.ABSTRACTBACKGROUND: The aging and dementia field has long been interested in understanding disease heterogeneity, subtypes, and progression. Work has progressed from clinical, to neuroimaging to biomedical devices to neuropathological data, and now brain and blood omic data.METHOD: The AMP-AD consortium generated and/or annotated genomic, epigenomic, transcriptomic, proteomic, and metabolomic data from brain and/or blood from thousands of study participants and patients across the 8 teams. They include women, men, non-Latino white and black, and Latinos, covering the full spectrum of clinical and neuropathologic traits and diseases. All data were deposited in the AD Knowlege Portal (www.synapse.org) and made available to the wider aging and dementia research community in an open science environment.RESULT: The omic data has been leveraged by members of the AMP-AD teams, the SAGE bionetworks team which manages the Portal, and the wider research community to address disease heterogeneity, subtypes, and progression at the molecular level. New computation tools and approaches were developed and/or adapted from the cancer space as such deep and varied brain omic data were not previously available from humans. Initial studies used a single layer of data. Later studies integrated two or more layers of data. Ongoing work is now bridging the gap to project blood omic data to molecular trajectories in the same humans. Examples of the work across this spectrum will be presented.CONCLUSION: The data generated and/or annotated in first decade of AMP-AD is now defining disease heterogeneity, subtypes, and progression at the molecular level in the brain and beginning to bridge the gap to data obtainable from living humans. It is hoped that this will move the field closer to a time when precision medicine for brain diseases can target brain molecular pathways.PMID:39750985 | DOI:10.1002/alz.086461

Alzheimers Dement. 2024 Dec;20 Suppl 1:e086622. doi: 10.1002/alz.086622.ABSTRACTBACKGROUND: While compelling evidence highlights the importance of myeloid cells in the etiology of Alzheimer's Disease (AD), the relevance of immunometabolism still requires further exploration. Our analysis integrating AD genetics and myeloid cell genomics shows that lower levels of LACTB expression in myeloid cells is protective against AD, a finding supported by proteomics studies. As a mitochondrial active-site serine protein, LACTB has implications for mitochondrial morphology and bioenergetics. LACTB levels are also linked to succinyl-carnitine levels, a metabolite predicted to be protective for AD risk. Furthermore, LACTB has been associated with tumorigenesis and obesity, suggesting a potential role in cell dynamics and lipid metabolism, although its function remains elusive.METHOD: Human immortalized THP-1 cells monocytes were differentiated into macrophages and treated with small-interfering RNA to knock-down LACTB (KD) expression. CRISPR-edited human induced pluripotent stem cells (hiPSC) were generated to knock-out (KO) LACTB and differentiated into microglia cells (iMGL). Metabolomic and lipidomic analyses were outsourced with collected samples, and functional assays evaluating how LACTB alters myeloid cell functions were performed.RESULT: Our studies revealed an upregulation of LACTB expression upon differentiation (in iMGLs compared to iPSCs, and in THP-1 macrophages compared to monocytes) and LPS stimulation. Downregulation of LACTB in THP-1s and iMGLs resulted in elevated succinyl-carnitine levels, and THP-1 LACTB KD cells showed an increase in histone succinylation levels, which might indicate epigenetic modulation. We also detected a reduction in nascent protein synthesis levels in our LACTB KD and KO models. Additionally, lipidomics showed a decrease in acylglycerides, and an increase in cholesterol efflux was observed in THP-1 LACTB KD cells.CONCLUSION: LACTB potentially modulates myeloid cell function by modifying protein synthesis and lipid metabolism. Future directions include a novel xenotransplantation model involving the direct introduction of human microglia precursor cells into the mouse brain to study the effects of LACTB on microglia in-vivo and in the context of disease using 5xFAD mice. The distinct identity of LACTB as an enzyme, coupled with its protective phenotype upon reduced expression and the potential of succinyl carnitine as a biomarker, makes it a promising therapeutic target in AD.PMID:39750941 | DOI:10.1002/alz.086622

Alzheimers Dement. 2024 Dec;20 Suppl 1:e092051. doi: 10.1002/alz.092051.ABSTRACTBACKGROUND: The integration of quantitative trait loci (QTLs) with disease genome-wide association studies (GWAS) has proven successful at prioritizing candidate genes at disease-associated loci. Most of QTL studies are focusing on expression QTLs in plasma and brain and cis-signals.METHOD: Here we analyzed a large proteomic (Somalogic 7K) and metabolomic (Metabolon HD4) CSF (n = 3, 000) and plasma (African (AFR, N = 400) and European (EUR, N = 2,300) ancestry, respectively) to identify novel QTLs. We integrated with FUSION, colocalization and Mendelian Randomization approaches to identify novel causal and druggable targets.RESULT: In CSF we identified 2,316 significant pQTLs (1,247 in cis and 1,069 in trans) for 1,960 proteins, of which 1,228 were not observed in plasma. For metabolomics we identified 219 independent associations (59.8% novel) for 144 CSF metabolites. In plasma, we identified 2,400 pQTL in EUR and 881 pQTL in AFR. In EUR and AFR metabolomics, we reported 403 and 60 metabolites with at least one significant QTL, respectively. Approximately 40% of these findings were novel associations compared to previous studies Through PWAS, we identified 473 CSF proteins associated with AD risk. MR prioritized 40 proteins as causal and colocalization identified 158 proteins that share genetic etiology. 42 of these overlap between at least two of these methods and are enriched in immune and lysosomal pathways. Multiple (including PILRA, PRSS8, and SIRPA) represent novel candidate proteins. We also identified novel regulators for TREM2 including TGBR2 and NECTIN2, which represent novel therapeutic targets for AD.CONCLUSION: We have developed the largest CSF proteomics and metabolomics data. Through a rigorous approach combining three methods, we have identified high-confidence proteins involved in AD that confirm previously reported candidate genes and prioritize new ones at GWAS loci. Our findings offer insights into Alzheimer's disease biology that were missing when using plasma analyses, supporting the development of tissue-specific proteomics databases in neurologically-relevant tissues.PMID:39750915 | DOI:10.1002/alz.092051

Alzheimers Dement. 2024 Dec;20 Suppl 1:e090912. doi: 10.1002/alz.090912.ABSTRACTBACKGROUND: Altered lipid profiles and lipid processing genes are associated with Alzheimer's disease (AD). There is a reported genetic interaction between the AD risk gene APOE and cholesterol ester transfer protein (CETP). Mice lack functional CETP which is critical to the balance of circulating lipoproteins; this imparts cardioprotective effects and may make mice resistant to AD. Additionally, previous studies in transgenic humanized CETP (hCETP) mice have demonstrated that CETP addition in mice increases expression of AD risk genes and markers of AD pathogenicity. Together, this suggests that CETP may modify AD risk in an APOE4-dependent manner. This project aims to determine molecular pathways and signatures in AD mediated by CETP with an emphasis on molecular pathways shared with APOE as a potential disease-altering mechanism.METHODS: To identify pathways shared by CETP and APOE we created molecular networks using publicly available online tools including the AD Atlas and STRING (v12.0). The Heart and Diabetes Institute Metabolomics Laboratory Portal was leveraged to perform Genome Wide Association Study (GWAS) analysis to establish changes in lipid species abundance shared by CETP and APOE genetic variants. Transcriptional signatures in several mouse models were compared to human AD gene modules to determine pathological relevance of hCETP and APOE4 mouse models.RESULTS: Molecular networks implicated several genes as being co-expressed suggesting they may co-function with CETP and APOE. These co-expression edges included C4A/B compliment genes, PSMB8, APOJ/CLU, and APP. GWAS analysis resulted in several notable findings including that CETP variants have a strong effect on the relative abundance of phosphatidylcholine (PC) lipid species. Additionally, while APOE4 is positively associated with total PC, the common loss-of-function variant CETP I405V (rs5882) is associated with reduced PC levels. Transcriptional changes in lipid-related transgenic and MODEL-AD knock-in mouse models exhibited significant associations with immune processes.CONCLUSIONS: These findings indicate that both CETP and APOE influence total PC and are associated with molecular pathways of immune activation and amyloid biology. Overall this evidence suggests that CETP and APOE act on shared pathways, likely mediated by lipid metabolism and peripheral immunity, that contribute to AD susceptibility.PMID:39750805 | DOI:10.1002/alz.090912

Alzheimers Dement. 2024 Dec;20 Suppl 1:e090015. doi: 10.1002/alz.090015.ABSTRACTBACKGROUND: Studies using Alzheimer's disease (AD) models suggest that gut bacteria contribute to amyloid pathology and systemic inflammation. Further, gut-derived metabolites serve critical roles in regulating cholesterol, blood-brain barrier permeability, neuroinflammation, and circadian rhythms. Recent studies from the Alzheimer's Disease Neuroimaging Initiative have shown that serum-based gut-derived metabolites are associated with AD biomarkers and cognitive impairment. We recently reported a time-restricted feeding (TRF) intervention that restored brain transcription, increased Aβ clearance, reduced amyloid deposition, and improved memory deficits in AD mice (PMID:37607543). Here we investigated gut microbiome alterations in the APP23 mouse stool and terminal ileum and evaluated the role of the microbiome and metabolome in the beneficial effects of TRF.METHODS: Adult male and female APP23 transgenic (TG) and littermate non-transgenic (NTG) mice (n = 3-4/sex/genotype/condition) underwent ad libitum feeding (ALF) or a TRF protocol consisting of 6-hours of active-phase feeding followed by 18-hours fasting for 3-months. Metabolomics, metagenomics and metatranscriptomics were performed on ileum and stool (collected every 4-hours for 24-hours) from mice used in our TRF intervention study.RESULTS: Metagenomic analyses revealed that the stool microbiome composition and genomic functions were altered in APP23 TG compared to NTG mice and were further uniquely modulated in TG mice on TRF. Notably, stool metabolites relating to metabolism and neuroimmune function were differentially abundant in TG mice and partially restored by TRF. The stool microbiome and metabolome presented distinct diurnal cycling dynamics. TG mice showed a significant loss of rhythmic genomes which were markedly increased by TRF, indicative of broad entrainment of microbial rhythmicity. Ileal diurnal dynamics further differentiated TG mice on TRF. Ileal metatranscriptomic analysis revealed that TRF also reversed bacterial compositional and functional alterations in TG mice, including the attenuation of elevated inflammation-related bacterial transcripts.CONCLUSIONS: TG mice showed alterations in microbiome composition, function, and rhythmicity. The unique microbiome induced by TRF regulated functions and metabolites implicated in AD and may represent one of the pathways by which TRF rescued pathology and cognition in AD mice.PMID:39750757 | DOI:10.1002/alz.090015

Alzheimers Dement. 2024 Dec;20 Suppl 1:e090001. doi: 10.1002/alz.090001.ABSTRACTBACKGROUND: Bile acids (BA) are steroids regulating nutrient absorption, energy metabolism, and mitochondrial function, and serve as important signaling molecules with a role in the gut-brain axis. The composition of BAs in humans changes with diet type and health status, which is well documented with a few known bile acids. In this study, we leveraged a new BA-specific spectral library curated in the Dorrestein lab at UCSD to expand the pool of detected BAs in Alzheimer-related LC-MS/MS datasets and provide links to dietary profiles and AD markers.METHOD: Fecal untargeted metabolomics (LC-MS/MS) data from the ADRC cohort was analyzed using GNPS-based molecular networking. Spectral matching and annotation were performed using the BA-specific spectral library which consists of 21,549 BA spectra, with many previously undiscovered candidates. We obtained spectral matches to 113 BAs with 108 matches to new candidate BAs from our library. Further, using the score for delayed recall of Benson figure (UDSBENTD), peak areas of the BAs were plotted with the amyloid status. For diet readout, spectral match to a food database ("global foodomics") was performed, and correlation with BAs was obtained by joint-RPCA analysis.RESULT: The joint-RPCA analysis yielded many di-, tri-, and tetrahydroxylated BAs among the top 20 features guiding the separation in the ADRC samples (Figure 1a). From diet, meat, fish, and fruits were among the top features, with meat and fish vectors pointing in the opposite direction as grapes, onions, and lettuce. Peak area-based levels of a candidate tetrahydroxylated BA, which was among the top 20 features, changed with the amyloid status measured with the UDSBENTD (Figure 1b). The spectral count of vegetables and dairy also increased in amyloid-positive samples. However, the spectral counts related to meat and poultry products did not change significantly with amyloid status, implying a potential vegetable-based diet impacting the change in some BA levels.CONCLUSION: Previously unknown BAs are correlated to diet and AD markers in the ADRC cohort. This study highlights the importance of expanding our metabolite annotations, in this case with BAs, and performing integrative analysis with diet to aid our understanding of AD progression.PMID:39750730 | DOI:10.1002/alz.090001

J Agric Food Chem. 2025 Jan 3. doi: 10.1021/acs.jafc.4c09492. Online ahead of print.ABSTRACTThe postingestion journey and bioconversion of wheat bran-bound ferulic acid, a known beneficial phytochemical, remain insufficiently understood. This study aims to systematically investigate its bioaccessibility, bioavailability, excretion, and colonic metabolism, both in vitro and in vivo. Initial analysis confirmed the abundance and bioactivity of ferulic acid in wheat bran. Using a simulated gastrointestinal model, 1.7% of the ferulic acid was found to be bioaccessible, in contrast to 43.4% for total phenolics. In vivo bioavailability was assessed in rats via oral gavage of cooked wheat bran, with a plasma ferulic acid level peaking at 32.5 ± 4.9 ng/mL, corresponding to an absorption rate of 0.3%, while 1% was excreted in urine. Fecal metabolomic analysis revealed extensive colonic bioconversion, with elevated levels of ferulic acid and its metabolites, including 3-phenylpropionic acid, dihydroferulic acid, 5-hydroxyferulic acid, and hippuric acid. Novel metabolites, such as 3-(2,5-dimethoxyphenyl)propionic acid and N-(2-furoyl)glycine, were detected for the first time. These findings shed light on the complex biotransformation of wheat bran-bound ferulic acid and its potential health implications.PMID:39750057 | DOI:10.1021/acs.jafc.4c09492

Int J Mol Med. 2025 Mar;55(3):38. doi: 10.3892/ijmm.2024.5479. Epub 2025 Jan 3.ABSTRACTAcute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an inflammatory response arising from lung and systemic injury with diverse causes and associated with high rates of morbidity and mortality. To date, no fully effective pharmacological therapies have been established and the relevant underlying mechanisms warrant elucidation, which may be facilitated by multi‑omics technology. The present review summarizes the application of multi‑omics technology in identifying novel diagnostic markers and therapeutic strategies of ALI/ARDS as well as its pathogenesis.PMID:39749711 | DOI:10.3892/ijmm.2024.5479

Mol Med Rep. 2025 Mar;31(3):65. doi: 10.3892/mmr.2025.13430. Epub 2025 Jan 3.ABSTRACTAseptic loosening (AL) of artificial hip joints is the most common complication following hip replacement surgery. A total of eight patients diagnosed with AL following total hip arthroplasty (THA) undergoing total hip replacement and eight control patients diagnosed with avascular necrosis of femoral head (ANFH) or femoral neck fracture undergoing THA were enrolled. The samples of the AL group were from synovial tissue surrounding the lining/head/neck of the prosthesis, and the samples of the control group were from the synovium in the joint cavity. The present study utilized second‑generation high‑throughput sequencing and mass spectrometry to detect differentially expressed genes, proteins and metabolites in the samples, as well as Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. Key genes cytokine receptor‑like factor‑1 (CRLF1) and glutathione‑S transferase µ1 (GSTM1) expression levels were verified by reverse transcription‑quantitative PCR and western blotting. The integrated transcriptomics, proteomics and untargeted metabolomics analyses revealed characteristic metabolite changes (biosynthesis of guanine, L‑glycine and adenosine) and decreased CRLF1 and GSTM1 in AL, which were primarily associated with amino acid metabolism and lipid metabolism. In summary, the present study may uncover the underlying mechanisms of AL pathology and provide stable and accurate biomarkers for early warning and diagnosis.PMID:39749710 | DOI:10.3892/mmr.2025.13430

CNS Neurosci Ther. 2025 Jan;31(1):e70203. doi: 10.1111/cns.70203.ABSTRACTBACKGROUND: Metabolomics offers promise in uncovering potential biomarkers and understanding the pathophysiology of autoimmune encephalitis (AE), which is a cluster of disorders with the host immune system targeting self-antigens expressed in the central nervous system (CNS). In this research, our objective was to explore metabolic characterization in cerebrospinal fluid (CSF) from individuals with AE, aiming to shed light on the pathophysiology of AE.METHODS: A targeted approach was applied using an ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) system to study CSF metabolites in patients with AE (n = 18), and control subjects without neurological diseases (n = 17).RESULTS: A total of 21 potential biomarkers were acquired by getting the intersection of the differential metabolites from univariate statistics and multidimensional statistics between the AE (cell-based assay panel, CBA-panel) group and the control group. Specifically, the levels of pyruvic acid and oxoglutaric acid were notably elevated in the AE(CBA-panel) group compared to those in the control group, indicating that the dysregulated TCA cycle may play a pivotal role in the progression of AE(CBA-panel). Interestingly, 27 potential biomarkers were acquired by getting the intersection of the differential metabolites from univariate statistics and multidimensional statistics between the anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) group and the control group, suggesting that the disparities between patients with greater homogeneity and the controls are amplified. In addition, seven differential metabolites were identified by the univariate statistics between the AE (tissue-based assay, TBA) group and the control group, including alpha-linolenic acid and gamma-linolenic acid, suggesting that dysregulated biosynthesis of unsaturated fatty acids and alpha-linolenic acid metabolism might be crucial in the AE(TBA) disease course.CONCLUSION: Collectively, distinct metabolic profiles were evident in the CSF of the AE group compared to the control group, notably involving metabolites associated with mitochondrial dysfunction, which helped to elucidate the pathophysiology of AE.PMID:39749658 | DOI:10.1111/cns.70203

Trans R Soc Trop Med Hyg. 2025 Jan 3:trae073. doi: 10.1093/trstmh/trae073. Online ahead of print.ABSTRACTSnake venom proteins have long been recognized for their therapeutic potential. Proteogenomic strategies, integrating transcriptomics and proteomics, have emerged as powerful tools for identifying and characterizing venom proteins for the development of novel therapeutic agents. Analytical techniques like mass spectrometry and next-generation sequencing enable comprehensive analysis, identifying key venom components and their variants. Recent studies unveil the diversity and complexity of snake venom, highlighting species-specific variations in toxin composition. Structural biology techniques, including x-ray crystallography and cryo-electron microscopy, provide insights into venom enzyme structures and mechanisms of action, facilitating drug design. Bioinformatics tools aid in data analysis and prediction of venom protein functions, enhancing drug discovery efforts. Despite advancements, challenges persist, including toxicity, formulation stability and clinical validation. This review describes the current as well as future options for research and development and emphasizes the critical role of proteogenomic techniques in developing snake venom protein-based drugs.PMID:39749538 | DOI:10.1093/trstmh/trae073

Front Microbiol. 2024 Dec 19;15:1477187. doi: 10.3389/fmicb.2024.1477187. eCollection 2024.ABSTRACTGut microbiota regulates the immune system, the development and progression of autoimmune diseases (AIDs) and overall health. Recent studies have played a crucial part in understanding the specific role of different gut bacterial strains and their metabolites in different AIDs. Microbial signatures in AIDs are revealed by advanced sequencing and metabolomics studies. Microbes such as Faecalibacterium prausnitzii, Akkermansia muciniphila, Anaerostipes caccae, Bacteroides sp., Roseburia sp., Blautia sp., Blautia faecis, Clostridium lavalense, Christensenellaceae sp., Coprococcus sp., Firmicutes sp., Ruminococcaceae sp., Lachnospiraceae sp., Megamonas sp., Monoglobus sp., Streptococcus pneumoniae and Bifidobacterium sp. help maintain immune homeostasis; whereas, Prevotella copri, Ruminococcus gnavus, Lactobacillus salivarius, Enterococcus gallinarum, Elizabeth menigoseptica, Collinsella sp., Escherichia sp., Fusobacterium sp., Enterobacter ludwigii, Enterobacteriaceae sp., Proteobacteria, Porphyromonas gingivalis, Porphyromonas nigrescens, Dorea sp., and Clostridium sp. cause immuno-pathogenesis. A complex web of interactions is revealed by understanding the influence of gut microbiota on immune cells and various T cell subsets such as CD4+ T cells, CD8+ T cells, natural killer T cells, γδ T cells, etc. Certain AIDs, including rheumatoid arthritis, diabetes mellitus, atopic asthma, inflammatory bowel disease and non-alcoholic fatty liver disease exhibit a state of dysbiosis, characterized by alterations in microbial diversity and relative abundance of specific taxa. This review summarizes recent developments in understanding the role of certain microbiota composition in specific AIDs, and the factors affecting specific regulatory T cells through certain microbial metabolites and also focuses the potential application and therapeutic significance of gut microbiota-based interventions as novel adjunctive therapies for AIDs. Further research to determine the precise association of each gut bacterial strain in specific diseases is required.PMID:39749132 | PMC:PMC11694513 | DOI:10.3389/fmicb.2024.1477187

Pulm Circ. 2025 Jan 2;15(1):e70027. doi: 10.1002/pul2.70027. eCollection 2025 Jan.ABSTRACTPulmonary vascular disease is not a single condition; rather it can accompany a variety of pathologies that impact the pulmonary vasculature. Applying precision medicine strategies to better phenotype, diagnose, monitor, and treat pulmonary vascular disease is increasingly possible with the growing accessibility of powerful clinical and research tools. Nevertheless, challenges exist in implementing these tools to optimal effect. The 2023 Grover Conference Series reviewed the research landscape to summarize the current state of the art and provide a better understanding of the application of precision medicine to managing pulmonary vascular disease. In particular, the following aspects were discussed: (1) Clinical phenotypes, (2) genetics, (3) epigenetics, (4) biomarker discovery, (5) application of precision biology to clinical trials, (6) the right ventricle (RV), and (7) integrating precision medicine to clinical care. The present review summarizes the content of these discussions and the prospects for the future.PMID:39749110 | PMC:PMC11693987 | DOI:10.1002/pul2.70027