Summary of Study ST004230
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002147. The data can be accessed directly via it's Project DOI: 10.21228/M83F9Q This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.
| Study ID | ST004230 |
| Study Title | Effect of ATV:4D9 on Microglial Metabolism and FDG levels in mKate-TREM2/APP mouse model |
| Study Summary | Targeted lipid and metabolite profiling was performed in microglia from mKate-TREM2/APP mice treated with ATV:4D9, a blood–brain barrier-penetrant TREM2 agonist antibody, following FDG injection to assess effects on glucose uptake. Microglia were isolated and sorted by fluorescent TREM2 reporter expression, enabling analysis of low-, mid-, and high-TREM2 subpopulations. LC-MS data show that the low TREM2 subpopulations derived from mice dosed chronically with ATV:4D9 and isotype control have similar lipidomic and metabolomic profiles, while the mid and high TREM2 subpopulations are distinct and cluster depending upon antibody dosing, suggesting that the TREM2 agonist antibody differentially modulates microglial metabolism dependent on TREM2 expression level. |
| Institute | Denali Therapeutics |
| Last Name | Suh |
| First Name | Jung |
| Address | 161 Oyster Point Blvd, South San Francisco, California, 94080, USA |
| suh@dnli.com | |
| Phone | +1 6507973837 |
| Submit Date | 2025-09-18 |
| Num Groups | 5 |
| Total Subjects | 26 |
| Num Males | 26 |
| Study Comments | Release as soon as it is possible |
| Publications | https://www.biorxiv.org/content/10.1101/2024.07.18.604115v1 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | mzML |
| Analysis Type Detail | LC-MS |
| Release Date | 2025-09-29 |
| Release Version | 1 |
Select appropriate tab below to view additional metadata details:
Project:
| Project ID: | PR002147 |
| Project DOI: | doi: 10.21228/M83F9Q |
| Project Title: | TREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism |
| Project Type: | Preclinical Mouse study |
| Project Summary: | Triggering receptor expressed on myeloid cells 2 (TREM2) is a central regulator of microglial activity and sequence variants are major risk factors for late onset Alzheimer’s disease (LOAD). To better understand the molecular and functional changes associated with TREM2 signalling, we generated a TREM2 reporter mouse model and observed a gradual upregulation of reporter expression with increasing plaque proximity. Isolated microglia were sorted based on reporter expression and their transcriptomic profiles acquired in both wildtype and APP transgenic animals, allowing us to disentangle TREM2 versus pathology-specific effects. Bulk RNA sequencing highlighted TREM2 level-dependent changes in major immunometabolic pathways, with enrichment of genes in oxidative phosphorylation and cholesterol metabolism in microglia with increased TREM2 expression. To confirm these findings, we next analysed uptake of fluorodeoxyglucose (FDG) and examined metabolomic and lipidomic profiles. Again, independent of Aβ pathology, TREM2 expression correlated with uptake of FDG as well as increased cellular redox, energetics, and cholesterol homeostasis. Finally, we performed chronic treatment with a brain penetrant TREM2 agonist and identified a window of TREM2 expression where microglia are most responsive. Thus, our data provide novel insights into TREM2-mediated regulation of microglial metabolic function and informs current efforts to bring TREM2 agonists into clinical application. |
| Institute: | Denali Therapeutics |
| Department: | Development Sciences |
| Last Name: | Suh |
| First Name: | Jung |
| Address: | 161 Oyster Point Blvd, South San Francisco, California, 94080, USA |
| Email: | suh@dnli.com |
| Phone: | +1 6507973837 |
| Funding Source: | Denali Therapeutics |
| Publications: | https://www.biorxiv.org/content/10.1101/2024.07.18.604115v1 |
Subject:
| Subject ID: | SU004382 |
| Subject Type: | Mammal |
| Subject Species: | Mus musculus |
| Taxonomy ID: | 10090 |
| Age Or Age Range: | 15 mo |
| Gender: | Male |
Factors:
Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)
| mb_sample_id | local_sample_id | condition | treatment | Sample source |
|---|---|---|---|---|
| SA486142 | HSA-000036734 | high | ATV 4D9 | microglia |
| SA486143 | HSA-000036731 | high | ATV 4D9 | microglia |
| SA486144 | HSA-000036735 | high | ATV 4D9 | microglia |
| SA486145 | HSA-000036733 | high | ATV 4D9 | microglia |
| SA486146 | HSA-000036738 | high | ATV 4D9 | microglia |
| SA486147 | HSA-000036729 | high | ATV 4D9 | microglia |
| SA486148 | HSA-000036730 | high | ATV Iso | microglia |
| SA486149 | HSA-000036737 | high | ATV Iso | microglia |
| SA486150 | HSA-000036736 | high | ATV Iso | microglia |
| SA486151 | HSA-000036739 | high | ATV Iso | microglia |
| SA486152 | HSA-000036728 | high | ATV Iso | microglia |
| SA486153 | HSA-000036732 | high | ATV Iso | microglia |
| SA486154 | HSA-000036707 | low | ATV 4D9 | microglia |
| SA486155 | HSA-000036714 | low | ATV 4D9 | microglia |
| SA486156 | HSA-000036705 | low | ATV 4D9 | microglia |
| SA486157 | HSA-000036711 | low | ATV 4D9 | microglia |
| SA486158 | HSA-000036710 | low | ATV 4D9 | microglia |
| SA486159 | HSA-000036709 | low | ATV 4D9 | microglia |
| SA486160 | HSA-000036708 | low | ATV Iso | microglia |
| SA486161 | HSA-000036713 | low | ATV Iso | microglia |
| SA486162 | HSA-000036704 | low | ATV Iso | microglia |
| SA486163 | HSA-000036706 | low | ATV Iso | microglia |
| SA486164 | HSA-000036715 | low | ATV Iso | microglia |
| SA486165 | HSA-000036712 | low | ATV Iso | microglia |
| SA486166 | HSA-000036726 | mid | ATV 4D9 | microglia |
| SA486167 | HSA-000036722 | mid | ATV 4D9 | microglia |
| SA486168 | HSA-000036719 | mid | ATV 4D9 | microglia |
| SA486169 | HSA-000036721 | mid | ATV 4D9 | microglia |
| SA486170 | HSA-000036717 | mid | ATV 4D9 | microglia |
| SA486171 | HSA-000036723 | mid | ATV 4D9 | microglia |
| SA486172 | HSA-000036727 | mid | ATV Iso | microglia |
| SA486173 | HSA-000036724 | mid | ATV Iso | microglia |
| SA486174 | HSA-000036716 | mid | ATV Iso | microglia |
| SA486175 | HSA-000036720 | mid | ATV Iso | microglia |
| SA486176 | HSA-000036725 | mid | ATV Iso | microglia |
| SA486177 | HSA-000036718 | mid | ATV Iso | microglia |
| SA486138 | HSA-000037077 | NA | NA | microglia |
| SA486139 | HSA-000037078 | NA | NA | microglia |
| SA486140 | HSA-000036740 | NA | NA | microglia |
| SA486141 | HSA-000036741 | NA | NA | microglia |
| Showing results 1 to 40 of 40 |
Collection:
| Collection ID: | CO004375 |
| Collection Summary: | Microglia isolation was performed using the Magnetic-activated cell sorting (MACS) system (Miltenyi Biotec). No CD11b enrichment step was performed as the intrinsic mKate2 reporter is only expressed in TREM2 expressing (microglia) cells. Hence, fluorescence-activated cell sorting was performed based on fluorescent TREM2 reporter expression, enabling analysis of low-, mid-, and high-expressing TREM2 subpopulations from the same mouse. |
| Sample Type: | microglia |
| Storage Conditions: | -80℃ |
Treatment:
| Treatment ID: | TR004391 |
| Treatment Summary: | Mice were treated with TREM2 agonist antibody (4D9) engineered to cross the blood brain barrier using an antibody transport vehicle (ATV:4D9). To determine the effect of this brain-penetrant antibody on microglial subpopulations stratified by TREM2 expression levels, mice were dosed monthly with 1 mg/kg ATV:4D9 or isotype control (ATV:Iso) for 4 months. In addition, 30 mg/kg of fluorodeoxyglucose (FDG) was dosed 1 hour before animal takedown to enable detection of FDG-monophosphate (FDG-MP) in sorted microglia. |
Sample Preparation:
| Sampleprep ID: | SP004388 |
| Sampleprep Summary: | Pellets from the sorted subpopulations were reconstituted on ice in 9:1 MeOH:water including internal standards, vortexed for 1 minute, and spun down for 5 minutes at 10,000 g. Supernatant was transferred to glass vial for analysis by LC-MS. |
Chromatography:
| Chromatography ID: | CH005345 |
| Instrument Name: | Agilent 1290 Infinity II |
| Column Name: | Waters ACQUITY UPLC BEH C18 (100 x 2.1mm,1.7um) |
| Column Temperature: | 55 |
| Flow Gradient: | 0.0-8.0 min from 45% B to 99% B, 8.0-9.0 min at 99% B, 9.0-9.1 min to 45% B, and 9.1-10.0 min at 45% B. |
| Flow Rate: | 0.25 mL/min |
| Solvent A: | 60% acetonitrile/40% water; 10 mM ammonium formate; 0.1% formic acid |
| Solvent B: | 90% isopropyl alcohol/10% acetonitrile; 10 mM ammonium formate; 0.1% formic acid |
| Chromatography Type: | Reversed phase |
| Chromatography ID: | CH005346 |
| Instrument Name: | Agilent 1290 Infinity II |
| Column Name: | Waters ACQUITY UPLC BEH C18 (100 x 2.1mm,1.7um) |
| Column Temperature: | 55 |
| Flow Gradient: | 0.0-8.0 min from 45% B to 99% B, 8.0-9.0 min at 99% B, 9.0-9.1 min to 45% B, and 9.1-10.0 min at 45% B. |
| Flow Rate: | 0.25 mL/min |
| Solvent A: | 60% acetonitrile/40% water; 10 mM ammonium acetate; 0.1% acetic acid |
| Solvent B: | 90% ATV:Isopropyl alcohol/10% acetonitrile; 10 mM ammonium acetate; 0.1% acetic acid |
| Chromatography Type: | Reversed phase |
| Chromatography ID: | CH005347 |
| Instrument Name: | Agilent 1290 Infinity II |
| Column Name: | Waters ACQUITY UPLC BEH Amide (150 x 2.1mm,1.7um) |
| Column Temperature: | 55 |
| Flow Gradient: | 0.0-8.0 min from 45% B to 99% B, 8.0-9.0 min at 99% B, 9.0-9.1 min to 45% B, and 9.1-10.0 min at 45% B. |
| Flow Rate: | 0.25 mL/min |
| Solvent A: | 60% acetonitrile/40% water;10 mM ammonium formate; 0.1% formic acid |
| Solvent B: | 90% isopropyl alcohol/ 10% acetonitrile;10 mM ammonium formate; 0.1% formic acid |
| Chromatography Type: | HILIC |
| Chromatography ID: | CH005348 |
| Instrument Name: | Agilent 1290 Infinity II |
| Column Name: | Imtakt Intrada Organic Acid ( 150 x 2 mm, 3um) |
| Column Temperature: | 55 |
| Flow Gradient: | 0.0-1.0 min at 0% B; 1.0-7.0 min to 100% B; 7.1 at 0% B; and 7.1-10 min at 0% B. |
| Flow Rate: | 0.20 mL/min |
| Solvent A: | 10% acetonitrile/90% water; 0.1% formic acid |
| Solvent B: | 10% acetonitrile/90% water; 100mM ammonium formate |
| Chromatography Type: | Ion exchange |
Analysis:
| Analysis ID: | AN007041 |
| Analysis Type: | MS |
| Chromatography ID: | CH005345 |
| Num Factors: | 7 |
| Num Metabolites: | 140 |
| Units: | normalized peak area |
| Analysis ID: | AN007042 |
| Analysis Type: | MS |
| Chromatography ID: | CH005346 |
| Num Factors: | 7 |
| Num Metabolites: | 119 |
| Units: | normalized peak area |
| Analysis ID: | AN007043 |
| Analysis Type: | MS |
| Chromatography ID: | CH005347 |
| Num Factors: | 7 |
| Num Metabolites: | 216 |
| Units: | normalized peak area |
| Analysis ID: | AN007044 |
| Analysis Type: | MS |
| Chromatography ID: | CH005348 |
| Num Factors: | 7 |
| Num Metabolites: | 59 |
| Units: | normalized peak area |
| Analysis ID: | AN007045 |
| Analysis Type: | MS |
| Chromatography ID: | CH005348 |
| Num Factors: | 7 |
| Num Metabolites: | 2 |
| Units: | normalized peak area |
