Summary of Study ST004223

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 PR002664. The data can be accessed directly via it's Project DOI: 10.21228/M89G28 This work is supported by NIH grant, U2C- DK119886. See: https://www.metabolomicsworkbench.org/about/howtocite.php

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Study IDST004223
Study TitleSulfatide deficiency-induced astrogliosis and myelin lipid dyshomeostasis are independent of Trem2-mediated microglial activation
Study SummaryThis study investigated how sulfatide (ST) deficiency, an early lipid alteration in Alzheimer’s disease (AD), drives neuroinflammation and lipid dyshomeostasis, and whether these processes depend on Trem2-mediated microglial signaling. Using ST-deficient mice with or without Trem2 knockout, the researchers found that ST loss consistently caused myelin lipid disruption, cognitive impairment, free water retention, and bladder enlargement—phenotypes that were independent of Trem2 and more severe in females. Trem2 deficiency reduced some transcriptomic inflammatory responses but did not alter astrogliosis or lipid losses at the protein level, suggesting that Trem2 primarily modulates microglial signaling but not astrocyte activation or lipid disruption. Overall, the findings highlight sulfatide deficiency as a key driver of lipid and glial imbalance, and suggest that preserving myelin lipid integrity and astrocyte balance may be more effective than solely targeting Trem2-mediated microglial activation in slowing AD progression.
Institute
UT Health San Antonio
Last NameHan
First NameXianlin
Address4939 Charles Katz Dr
Emailhanx@uthscsa.edu
Phone2105624104
Submit Date2025-09-09
Raw Data AvailableYes
Raw Data File Type(s)mzML, raw(Thermo)
Analysis Type DetailMS(Dir. Inf.)
Release Date2025-09-28
Release Version1
Xianlin Han Xianlin Han
https://dx.doi.org/10.21228/M89G28
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR002664
Project DOI:doi: 10.21228/M89G28
Project Title:Sulfatide deficiency-induced alterations in myelin lipids are independent of Trem2
Project Summary:Disrupted lipid homeostasis and neuroinflammation often co-exist in neurodegenerative disorders including Alzheimer’s disease (AD). However, the intrinsic connection and causal relationship between these deficits remain elusive. Our previous studies show that the loss of sulfatide (ST), a class of myelin-enriched lipids, causes AD-like neuroinflammatory responses, cognitive impairment, bladder enlargement, and lipid dyshomeostasis. To better understand the relationship between neuroinflammation and lipid disruption induced by ST deficiency, we established a ST-deficient mouse model with a constitutive Trem2 knockout. Our study demonstrated that Trem2 regulates ST deficiency-induced neuroinflammation and astrocyte activation at the transcriptomic level but does not affect stage 1 disease-associated microglia or astrogliosis at the protein level. Additionally, ST loss-induced lipidome disruption, free water retention, and cognitive impairment were consistently observed in the absence of Trem2. Further, these phenotypes were more severe in females compared to males. Collectively, these results emphasize the essential role of Trem2 in mediating lipid loss-associated microglia mediated neuroinflammation, but not astrogliosis or myelin lipid disruption. Moreover, we demonstrated that attenuating Trem2-mediated neuroinflammation has a limited impact on brain ST loss-induced lipidome alteration or AD-like central and peripheral disorders. Our findings suggest that preserving the lipidome and astrocyte balance may be crucial in decelerating the progression of AD.
Institute:UT Health San Antonio
Last Name:Han
First Name:Xianlin
Address:4939 Charles Katz Dr, San Antonio, TX
Email:hanx@uthscsa.edu
Phone:2105624104

Subject:

Subject ID:SU004375
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090

Factors:

Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Sample source genotype
SA485912Female_CRM_Cre+4mouse cerebrum Cre+
SA485913Female_CRM_Cre+7mouse cerebrum Cre+
SA485914Female_CRM_Cre+6mouse cerebrum Cre+
SA485915Female_CRM_Cre+5mouse cerebrum Cre+
SA485916Female_CRM_Cre+1mouse cerebrum Cre+
SA485917Female_CRM_Cre+2mouse cerebrum Cre+
SA485918Female_CRM_Cre+3mouse cerebrum Cre+
SA485919Female_CRM_Cre-2mouse cerebrum Cre-
SA485920Female_CRM_Cre-1mouse cerebrum Cre-
SA485921Female_CRM_Cre-6mouse cerebrum Cre-
SA485922Female_CRM_Cre-5mouse cerebrum Cre-
SA485923Female_CRM_Cre-3mouse cerebrum Cre-
SA485924Female_CRM_Cre-4mouse cerebrum Cre-
SA485925Female_CRM_Trem2 KO/Cre+1mouse cerebrum Trem2 KO/Cre+
SA485926Female_CRM_Trem2 KO/Cre+2mouse cerebrum Trem2 KO/Cre+
SA485927Female_CRM_Trem2 KO/Cre+3mouse cerebrum Trem2 KO/Cre+
SA485928Female_CRM_Trem2 KO/Cre+4mouse cerebrum Trem2 KO/Cre+
SA485929Female_CRM_Trem2 KO/Cre-1mouse cerebrum Trem2 KO/Cre-
SA485930Female_CRM_Trem2 KO/Cre-3mouse cerebrum Trem2 KO/Cre-
SA485931Female_CRM_Trem2 KO/Cre-4mouse cerebrum Trem2 KO/Cre-
SA485932Female_CRM_Trem2 KO/Cre-5mouse cerebrum Trem2 KO/Cre-
SA485933Female_CRM_Trem2 KO/Cre-2mouse cerebrum Trem2 KO/Cre-
SA485934Male_SC_Cre+9mouse spinal cord Cre+
SA485935Female_SC_Cre+2mouse spinal cord Cre+
SA485936Female_SC_Cre+3mouse spinal cord Cre+
SA485937Female_SC_Cre+4mouse spinal cord Cre+
SA485938Female_SC_Cre+11mouse spinal cord Cre+
SA485939Female_SC_Cre+5mouse spinal cord Cre+
SA485940Female_SC_Cre+6mouse spinal cord Cre+
SA485941Female_SC_Cre+7mouse spinal cord Cre+
SA485942Female_SC_Cre+12mouse spinal cord Cre+
SA485943Male_SC_Cre+7mouse spinal cord Cre+
SA485944Female_SC_Cre+10mouse spinal cord Cre+
SA485945Female_SC_Cre+9mouse spinal cord Cre+
SA485946Male_SC_Cre+8mouse spinal cord Cre+
SA485947Male_SC_Cre+2mouse spinal cord Cre+
SA485948Male_SC_Cre+6mouse spinal cord Cre+
SA485949Male_SC_Cre+5mouse spinal cord Cre+
SA485950Male_SC_Cre+4mouse spinal cord Cre+
SA485951Male_SC_Cre+3mouse spinal cord Cre+
SA485952Female_SC_Cre+8mouse spinal cord Cre+
SA485953Female_SC_Cre+1mouse spinal cord Cre+
SA485954Male_SC_Cre+1mouse spinal cord Cre+
SA485955Female_SC_Cre-10mouse spinal cord Cre-
SA485956Female_SC_Cre-9mouse spinal cord Cre-
SA485957Female_SC_Cre-8mouse spinal cord Cre-
SA485958Female_SC_Cre-1mouse spinal cord Cre-
SA485959Female_SC_Cre-2mouse spinal cord Cre-
SA485960Female_SC_Cre-3mouse spinal cord Cre-
SA485961Female_SC_Cre-4mouse spinal cord Cre-
SA485962Female_SC_Cre-5mouse spinal cord Cre-
SA485963Female_SC_Cre-6mouse spinal cord Cre-
SA485964Male_SC_Cre-8mouse spinal cord Cre-
SA485965Male_SC_Cre-6mouse spinal cord Cre-
SA485966Male_SC_Cre-1mouse spinal cord Cre-
SA485967Male_SC_Cre-2mouse spinal cord Cre-
SA485968Male_SC_Cre-3mouse spinal cord Cre-
SA485969Male_SC_Cre-4mouse spinal cord Cre-
SA485970Female_SC_Cre-7mouse spinal cord Cre-
SA485971Male_SC_Cre-9mouse spinal cord Cre-
SA485972Male_SC_Cre-5mouse spinal cord Cre-
SA485973Male_SC_Cre-7mouse spinal cord Cre-
SA485974Female_SC_Trem2 KO/Cre+1mouse spinal cord Trem2 KO/Cre+
SA485975Female_SC_Trem2 KO/Cre+2mouse spinal cord Trem2 KO/Cre+
SA485976Female_SC_Trem2 KO/Cre+6mouse spinal cord Trem2 KO/Cre+
SA485977Female_SC_Trem2 KO/Cre+5mouse spinal cord Trem2 KO/Cre+
SA485978Female_SC_Trem2 KO/Cre+4mouse spinal cord Trem2 KO/Cre+
SA485979Female_SC_Trem2 KO/Cre+3mouse spinal cord Trem2 KO/Cre+
SA485980Female_SC_Trem2 KO/Cre+7mouse spinal cord Trem2 KO/Cre+
SA485981Male_SC_Trem2 KO/Cre+7mouse spinal cord Trem2 KO/Cre+
SA485982Male_SC_Trem2 KO/Cre+14mouse spinal cord Trem2 KO/Cre+
SA485983Male_SC_Trem2 KO/Cre+5mouse spinal cord Trem2 KO/Cre+
SA485984Male_SC_Trem2 KO/Cre+13mouse spinal cord Trem2 KO/Cre+
SA485985Male_SC_Trem2 KO/Cre+1mouse spinal cord Trem2 KO/Cre+
SA485986Male_SC_Trem2 KO/Cre+3mouse spinal cord Trem2 KO/Cre+
SA485987Male_SC_Trem2 KO/Cre+4mouse spinal cord Trem2 KO/Cre+
SA485988Male_SC_Trem2 KO/Cre+2mouse spinal cord Trem2 KO/Cre+
SA485989Male_SC_Trem2 KO/Cre+6mouse spinal cord Trem2 KO/Cre+
SA485990Male_SC_Trem2 KO/Cre+9mouse spinal cord Trem2 KO/Cre+
SA485991Male_SC_Trem2 KO/Cre+10mouse spinal cord Trem2 KO/Cre+
SA485992Male_SC_Trem2 KO/Cre+11mouse spinal cord Trem2 KO/Cre+
SA485993Male_SC_Trem2 KO/Cre+12mouse spinal cord Trem2 KO/Cre+
SA485994Male_SC_Trem2 KO/Cre+8mouse spinal cord Trem2 KO/Cre+
SA485995Female_SC_Trem2 KO/Cre-8mouse spinal cord Trem2 KO/Cre-
SA485996Male_SC_Trem2 KO/Cre-1mouse spinal cord Trem2 KO/Cre-
SA485997Male_SC_Trem2 KO/Cre-2mouse spinal cord Trem2 KO/Cre-
SA485998Male_SC_Trem2 KO/Cre-3mouse spinal cord Trem2 KO/Cre-
SA485999Male_SC_Trem2 KO/Cre-4mouse spinal cord Trem2 KO/Cre-
SA486000Male_SC_Trem2 KO/Cre-5mouse spinal cord Trem2 KO/Cre-
SA486001Male_SC_Trem2 KO/Cre-6mouse spinal cord Trem2 KO/Cre-
SA486002Male_SC_Trem2 KO/Cre-7mouse spinal cord Trem2 KO/Cre-
SA486003Female_SC_Trem2 KO/Cre-5mouse spinal cord Trem2 KO/Cre-
SA486004Female_SC_Trem2 KO/Cre-7mouse spinal cord Trem2 KO/Cre-
SA486005Female_SC_Trem2 KO/Cre-6mouse spinal cord Trem2 KO/Cre-
SA486006Female_SC_Trem2 KO/Cre-4mouse spinal cord Trem2 KO/Cre-
SA486007Female_SC_Trem2 KO/Cre-3mouse spinal cord Trem2 KO/Cre-
SA486008Female_SC_Trem2 KO/Cre-2mouse spinal cord Trem2 KO/Cre-
SA486009Male_SC_Trem2 KO/Cre-8mouse spinal cord Trem2 KO/Cre-
SA486010Male_SC_Trem2 KO/Cre-9mouse spinal cord Trem2 KO/Cre-
SA486011Male_SC_Trem2 KO/Cre-10mouse spinal cord Trem2 KO/Cre-
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Collection:

Collection ID:CO004368
Collection Summary:Animal experiments were conducted in accordance with the ‘Guide for the Care and Use of Laboratory Animals’ (8th edition, National Research Council of the National Academies, 2011). The animal protocol was approved by the Institutional Animal Care and Use Committee (protocol code 20180044AP and approved on 01-09-2019). Cerebrum (from the right hemisphere) and spinal cord tissues were collected immediately after dissection. Tissues were visually inspected to exclude any samples with obvious signs of damage. Only intact, grossly normal-appearing specimens were included in the study. Each specimen was rapidly snap-frozen in liquid nitrogen and stored at –80 °C until further use.
Sample Type:Brain

Treatment:

Treatment ID:TR004384
Treatment Summary:The CST fl/fl mice were generated by Applied Stem Cell, Inc. using CRISPR technology to inject C57BL/6 embryos as previously described [1]. The Plp1-CreERT and Trem2 KO mouse lines were both purchased from JAX (stock #005975 and #027197, respectively). The CST fl/fl mice were crossed with Plp1-CreERT+ mice to generate conditional ST-deficient (Cre+) mice along with their respective (Cre-) controls as previously described. The constitutive Trem2 KO mice were crossed with ST-deficient Cre+ mice to generate Trem2 KO deficient mice (Trem2, CST fl/fl/Plp1-CreERT+) denoted as (KO/Cre+) along with the control (KO/Cre-).  [1] Qiu, S. et al. Adult-onset CNS myelin sulfatide deficiency is sufficient to cause Alzheimer's disease-like neuroinflammation and cognitive impairment. Mol Neurodegener 16, 64 (2021).

Sample Preparation:

Sampleprep ID:SP004381
Sampleprep Summary:Pulverized frozen CRM and SC tissues were homogenized ice-cold phosphate-buffered saline using a Precellys® Evolution Tissue Homogenizer (Bertin, France). The protein concentration of homogenates was determined using the Pierce BCA Protein Assay Kit (Thermo Fisher Scientific) following the manufacturer’s protocol. Lipids were extracted by the modified procedure of Bligh and Dyer in the presence of internal standards that were added based on the total protein content of each sample.

Combined analysis:

Analysis ID AN007026 AN007027 AN007028
Chromatography ID CH005335 CH005335 CH005335
MS ID MS006723 MS006724 MS006725
Analysis type MS MS MS
Chromatography type None (Direct infusion) None (Direct infusion) None (Direct infusion)
Chromatography system none none none
Column none none none
MS Type ESI ESI ESI
MS instrument type Triple quadrupole Triple quadrupole Orbitrap
MS instrument name Thermo TSQ Altis Thermo TSQ Altis Thermo Q Exactive Focus
Ion Mode POSITIVE NEGATIVE NEGATIVE
Units nmol/mg protein nmol/mg protein nmol/mg protein

Chromatography:

Chromatography ID:CH005335
Instrument Name:none
Column Name:none
Column Temperature:NA
Flow Gradient:NA
Flow Rate:NA
Solvent A:NA
Solvent B:NA
Chromatography Type:None (Direct infusion)

MS:

MS ID:MS006723
Analysis ID:AN007026
Instrument Name:Thermo TSQ Altis
Instrument Type:Triple quadrupole
MS Type:ESI
MS Comments:Mass spectrometric analysis was performed on a triple quadrupole mass spectrometer (TSQ Altis, Thermo Fisher Scientific, SanJose, CA), which is equipped with an automated nanospray device (TriVersa NanoMate, Advion Bioscience Ltd., Ithaca, NY) asdescribed [1]. Identification and quantification of lipid species were performed using an automated software program [2, 3]. In shotgun lipidomics, the terms positive mode and negative mode refer to the polarity of ionization used during electrosprayionization (ESI), which directly influences the types of lipids detected and how well they are characterized. Positive ion modegenerates positively charged ions and is best for detecting neutral and zwitterionic lipids, such as PC, SM, LPC, LPE, CBS, and CAR in this study. Data processing (e.g., ion peak selection, baseline correction, data transfer, peak intensity comparison andquantitation) was performed as described [3]. [1] Han, X., K. Yang, and R.W. Gross, Microfluidics-based electrospray ionizationenhances the intrasource separation of lipid classes and extends identification of individual molecular species through multi-dimensional mass spectrometry: development of an automated high-throughput platform for shotgun lipidomics. Rapid CommunMass Spectrom, 2008. 22(13): p. 2115-24. [2] Wang, M., et al., Novel advances in shotgun lipidomics for biology and medicine. ProgLipid Res, 2016. 61: p. 83-108. [3] Yang, K., et al., Automated lipid identification and quantification by multidimensional massspectrometry-based shotgun lipidomics. Anal Chem, 2009. 81(11): p. 4356-68. (NOTE: Associated raw data files are PC-1~101 and CAR-1~101)
Ion Mode:POSITIVE
  
MS ID:MS006724
Analysis ID:AN007027
Instrument Name:Thermo TSQ Altis
Instrument Type:Triple quadrupole
MS Type:ESI
MS Comments:Mass spectrometric analysis was performed on a triple quadrupole mass spectrometer (TSQ Altis, Thermo Fisher Scientific, SanJose, CA), which is equipped with an automated nanospray device (TriVersa NanoMate, Advion Bioscience Ltd., Ithaca, NY) asdescribed [1]. Identification and quantification of lipid species were performed using an automated software program [2, 3]. Inshotgun lipidomics, the terms positive mode and negative mode refer to the polarity of ionization used during electrosprayionization (ESI), which directly influences the types of lipids detected and how well they are characterized. Negative ion modegenerates negatively charged ions and is optimal for detecting anionic lipids, such as PE and Cer in this study. Data processing (e.g., ion peakselection, baseline correction, data transfer, peak intensity comparison and quantitation) was performed as described [3]. [1] Han,X., K. Yang, and R.W. Gross, Microfluidics-based electrospray ionization enhances the intrasource separation of lipid classes andextends identification of individual molecular species through multi-dimensional mass spectrometry: development of an automatedhigh-throughput platform for shotgun lipidomics. Rapid Commun Mass Spectrom, 2008. 22(13): p. 2115-24. [2] Wang, M., et al.,Novel advances in shotgun lipidomics for biology and medicine. Prog Lipid Res, 2016. 61: p. 83-108. [3] Yang, K., et al., Automatedlipid identification and quantification by multidimensional mass spectrometry-based shotgun lipidomics. Anal Chem, 2009. 81(11):p. 4356-68. (NOTE: Associated raw data files are PE-1~101, CER-1~101)
Ion Mode:NEGATIVE
  
MS ID:MS006725
Analysis ID:AN007028
Instrument Name:Thermo Q Exactive Focus
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Mass spectrometric analysis was performed on a Q Exactive mass spectrometer (Thermo Scientific, San Jose, CA), which isequipped with an automated nanospray device (TriVersa NanoMate, Advion Bioscience Ltd., Ithaca, NY) as described [1].Identification and quantification of lipid species were performed using an automated software program [2, 3]. We used a Thermo QExactive instrument for detection of CL, LCL, PS, ST, PA, PI, PG and BMP detection in this study. This hybrid quadrupole-Orbitrap massspectrometer offers high resolution, enables high-quality MS/MS fragmentation for structural analysis, and allows for detection of abroad range of lipid classes. Data processing (e.g., ion peak selection, baseline correction, data transfer, peak intensity comparisonand quantitation) was performed as described [3]. [1] Han, X., K. Yang, and R.W. Gross, Microfluidics-based electrospray ionizationenhances the intrasource separation of lipid classes and extends identification of individual molecular species through multi-dimensional mass spectrometry: development of an automated high-throughput platform for shotgun lipidomics. Rapid CommunMass Spectrom, 2008. 22(13): p. 2115-24. [2] Wang, M., et al., Novel advances in shotgun lipidomics for biology and medicine. ProgLipid Res, 2016. 61: p. 83-108. [3] Yang, K., et al., Automated lipid identification and quantification by multidimensional massspectrometry-based shotgun lipidomics. Anal Chem, 2009. 81(11): p. 4356-68. (NOTE: Associated raw data files are 1~101)
Ion Mode:NEGATIVE
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