Summary of Study ST003501

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.

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Study IDST003501
Study TitleTREM2 expression level is critical for microglial state, metabolic capacity and efficacy of TREM2 agonism
Study SummaryTriggering 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
Last NameSuh
First NameJung
Address161 Oyster Point Blvd, South San Francisco, California, 94080, USA
Emailsuh@dnli.com
Phone+1 6507973837
Submit Date2024-09-19
Num Groups5
Total Subjects26
Num Males26
Study CommentsRelease as soon as it is possible
Publicationshttps://www.biorxiv.org/content/10.1101/2024.07.18.604115v1
Raw Data AvailableYes
Raw Data File Type(s)mzML
Analysis Type DetailLC-MS
Release Date2024-09-30
Release Version1
Jung Suh Jung Suh
https://dx.doi.org/10.21228/M83F9Q
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Combined analysis:

Analysis ID AN005746 AN005747 AN005748 AN005749
Analysis type MS MS MS MS
Chromatography type Reversed phase Reversed phase HILIC Ion exchange
Chromatography system Agilent 1290 Infinity II Agilent 1290 Infinity II Agilent 1290 Infinity II Agilent 1290 Infinity II
Column Waters ACQUITY UPLC BEH C18 (100 x 2.1mm,1.7um) Waters ACQUITY UPLC BEH C18 (100 x 2.1mm,1.7um) Waters ACQUITY UPLC BEH Amide (150 x 2.1mm,1.7um) Imtakt Intrada Organic Acid (150 x 2mm, 3um) )
MS Type ESI ESI ESI ESI
MS instrument type Triple quadrupole Triple quadrupole Triple quadrupole Triple quadrupole
MS instrument name ABI Sciex 6500+ Qtrap ABI Sciex 6500+ Qtrap ABI Sciex 6500+ Qtrap ABI Sciex 6500+ Qtrap
Ion Mode POSITIVE POSITIVE POSITIVE NEGATIVE
Units log2(area) log2(area) log2(area) log2(area)
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