Summary of Study ST002453

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 PR001580. The data can be accessed directly via it's Project DOI: 10.21228/M8G711 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.

Perform statistical analysis  |  Show all samples  |  Show named metabolites  |  Download named metabolite data  
Download mwTab file (text)   |  Download mwTab file(JSON)   |  Download data files (Contains raw data)
Study IDST002453
Study TitleAPOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge (Part 3 of 3)
Study SummaryThe E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response – two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNAseq highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1α expression, a disrupted TCA cycle, and are inherently pro-glycolytic, while spatial transcriptomics and MALDI mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism.
Institute
University of Kentucky
DepartmentPhysiology
LaboratoryLance Johnson; Josh Morganti
Last NameDevanney
First NameNicholas
AddressPhysiology, 760 Press Ave, Healthy Kentucky Research Bldg, Rm152, Lexington, Kentucky, 40508, USA
EmailNicholas.Devanney@uky.edu
Phone8593238083
Submit Date2022-11-14
Raw Data AvailableYes
Raw Data File Type(s)raw(Waters)
Analysis Type DetailMALDI-MS
Release Date2023-01-25
Release Version1
Nicholas Devanney Nicholas Devanney
https://dx.doi.org/10.21228/M8G711
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:


Project:

Project ID:PR001580
Project DOI:doi: 10.21228/M8G711
Project Title:APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge
Project Summary:The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response – two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNAseq highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1α expression, a disrupted TCA cycle, and are inherently pro-glycolytic, while spatial transcriptomics and MALDI mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism.
Institute:University of Kentucky, Department of Physiology
Last Name:Devanney
First Name:Nicholas
Address:Physiology, 760 Press Ave, Healthy Kentucky Research Bldg, Rm152, Lexington, Kentucky, 40508, USA
Email:Nicholas.Devanney@uky.edu
Phone:8593238083
Project Comments:Part 2 of 3

Subject:

Subject ID:SU002542
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090
Genotype Strain:APOE-targeted replacement mice homozygous for human E3 (B6.129P2-Apoe^tm2(APOE*3)Mae N8, Taconic #1548-F) or human E4 (B6.129P2- Apoe^tm3(APOE*4)Mae N8, Taconic #1549-F) alleles and crossed to the 5x Familial Alzheimer's Disease (5XFAD) model (MMRRC #34840, B6SJL^Tg( APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax))
Age Or Age Range:3 months, 12 months, 24 months
Gender:Female

Factors:

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

mb_sample_id local_sample_id Brain Region Group APOE genotype 5XFAD Genotype Age
SA245312JJ3_73_Cerebral NucleiCerebral Nuclei E3_FAD E3/E3 Hemizygous 12 months
SA245313JJ3_76_Cerebral NucleiCerebral Nuclei E3_FAD E3/E3 Hemizygous 12 months
SA245314JJ3_66_Cerebral NucleiCerebral Nuclei E3_FAD E3/E3 Hemizygous 12 months
SA245315B427_Cerebral NucleiCerebral Nuclei E3_old E3/E3 Wild-type 24 months
SA245316B354_Cerebral NucleiCerebral Nuclei E3_old E3/E3 Wild-type 24 months
SA245317B425_Cerebral NucleiCerebral Nuclei E3_old E3/E3 Wild-type 24 months
SA245318B647_Cerebral NucleiCerebral Nuclei E3_young E3/E3 Wild-type 3 months
SA245319B648_Cerebral NucleiCerebral Nuclei E3_young E3/E3 Wild-type 3 months
SA245320B652_Cerebral NucleiCerebral Nuclei E3_young E3/E3 Wild-type 3 months
SA245321KK4_116_Cerebral NucleiCerebral Nuclei E4_FAD E4/E4 Hemizygous 12 months
SA245322KK4_96_Cerebral NucleiCerebral Nuclei E4_FAD E4/E4 Hemizygous 12 months
SA245323KK4_40_Cerebral NucleiCerebral Nuclei E4_FAD E4/E4 Hemizygous 12 months
SA245324C202_Cerebral NucleiCerebral Nuclei E4_old E4/E4 Wild-type 24 months
SA245325C384_Cerebral NucleiCerebral Nuclei E4_old E4/E4 Wild-type 24 months
SA245326C362_Cerebral NucleiCerebral Nuclei E4_old E4/E4 Wild-type 24 months
SA245327C763_Cerebral NucleiCerebral Nuclei E4_young E4/E4 Wild-type 3 months
SA245328C762_Cerebral NucleiCerebral Nuclei E4_young E4/E4 Wild-type 3 months
SA245329C761_Cerebral NucleiCerebral Nuclei E4_young E4/E4 Wild-type 3 months
SA245330JJ3_73_Cortical SubplateCortical Subplate E3_FAD E3/E3 Hemizygous 12 months
SA245331JJ3_76_Cortical SubplateCortical Subplate E3_FAD E3/E3 Hemizygous 12 months
SA245332JJ3_66_Cortical SubplateCortical Subplate E3_FAD E3/E3 Hemizygous 12 months
SA245333B425_Cortical SubplateCortical Subplate E3_old E3/E3 Wild-type 24 months
SA245334B354_Cortical SubplateCortical Subplate E3_old E3/E3 Wild-type 24 months
SA245335B427_Cortical SubplateCortical Subplate E3_old E3/E3 Wild-type 24 months
SA245336B647_Cortical SubplateCortical Subplate E3_young E3/E3 Wild-type 3 months
SA245337B648_Cortical SubplateCortical Subplate E3_young E3/E3 Wild-type 3 months
SA245338B652_Cortical SubplateCortical Subplate E3_young E3/E3 Wild-type 3 months
SA245339KK4_96_Cortical SubplateCortical Subplate E4_FAD E4/E4 Hemizygous 12 months
SA245340KK4_116_Cortical SubplateCortical Subplate E4_FAD E4/E4 Hemizygous 12 months
SA245341KK4_40_Cortical SubplateCortical Subplate E4_FAD E4/E4 Hemizygous 12 months
SA245342C202_Cortical SubplateCortical Subplate E4_old E4/E4 Wild-type 24 months
SA245343C362_Cortical SubplateCortical Subplate E4_old E4/E4 Wild-type 24 months
SA245344C384_Cortical SubplateCortical Subplate E4_old E4/E4 Wild-type 24 months
SA245345C763_Cortical SubplateCortical Subplate E4_young E4/E4 Wild-type 3 months
SA245346C762_Cortical SubplateCortical Subplate E4_young E4/E4 Wild-type 3 months
SA245347C761_Cortical SubplateCortical Subplate E4_young E4/E4 Wild-type 3 months
SA245348JJ3_66_Fiber TractsFiber Tracts E3_FAD E3/E3 Hemizygous 12 months
SA245349JJ3_73_Fiber TractsFiber Tracts E3_FAD E3/E3 Hemizygous 12 months
SA245350JJ3_76_Fiber TractsFiber Tracts E3_FAD E3/E3 Hemizygous 12 months
SA245351B427_Fiber TractsFiber Tracts E3_old E3/E3 Wild-type 24 months
SA245352B425_Fiber TractsFiber Tracts E3_old E3/E3 Wild-type 24 months
SA245353B354_Fiber TractsFiber Tracts E3_old E3/E3 Wild-type 24 months
SA245354B648_Fiber TractsFiber Tracts E3_young E3/E3 Wild-type 3 months
SA245355B647_Fiber TractsFiber Tracts E3_young E3/E3 Wild-type 3 months
SA245356B652_Fiber TractsFiber Tracts E3_young E3/E3 Wild-type 3 months
SA245357KK4_40_Fiber TractsFiber Tracts E4_FAD E4/E4 Hemizygous 12 months
SA245358KK4_116_Fiber TractsFiber Tracts E4_FAD E4/E4 Hemizygous 12 months
SA245359KK4_96_Fiber TractsFiber Tracts E4_FAD E4/E4 Hemizygous 12 months
SA245360C384_Fiber TractsFiber Tracts E4_old E4/E4 Wild-type 24 months
SA245361C202_Fiber TractsFiber Tracts E4_old E4/E4 Wild-type 24 months
SA245362C362_Fiber TractsFiber Tracts E4_old E4/E4 Wild-type 24 months
SA245363C762_Fiber TractsFiber Tracts E4_young E4/E4 Wild-type 3 months
SA245364C763_Fiber TractsFiber Tracts E4_young E4/E4 Wild-type 3 months
SA245365C761_Fiber TractsFiber Tracts E4_young E4/E4 Wild-type 3 months
SA245366JJ3_66_HippocampusHippocampus E3_FAD E3/E3 Hemizygous 12 months
SA245367JJ3_73_HippocampusHippocampus E3_FAD E3/E3 Hemizygous 12 months
SA245368JJ3_76_HippocampusHippocampus E3_FAD E3/E3 Hemizygous 12 months
SA245369B425_HippocampusHippocampus E3_old E3/E3 Wild-type 24 months
SA245370B354_HippocampusHippocampus E3_old E3/E3 Wild-type 24 months
SA245371B427_HippocampusHippocampus E3_old E3/E3 Wild-type 24 months
SA245372B652_HippocampusHippocampus E3_young E3/E3 Wild-type 3 months
SA245373B647_HippocampusHippocampus E3_young E3/E3 Wild-type 3 months
SA245374B648_HippocampusHippocampus E3_young E3/E3 Wild-type 3 months
SA245375KK4_116_HippocampusHippocampus E4_FAD E4/E4 Hemizygous 12 months
SA245376KK4_96_HippocampusHippocampus E4_FAD E4/E4 Hemizygous 12 months
SA245377KK4_40_HippocampusHippocampus E4_FAD E4/E4 Hemizygous 12 months
SA245378C384_HippocampusHippocampus E4_old E4/E4 Wild-type 24 months
SA245379C202_HippocampusHippocampus E4_old E4/E4 Wild-type 24 months
SA245380C362_HippocampusHippocampus E4_old E4/E4 Wild-type 24 months
SA245381C761_HippocampusHippocampus E4_young E4/E4 Wild-type 3 months
SA245382C762_HippocampusHippocampus E4_young E4/E4 Wild-type 3 months
SA245383C763_HippocampusHippocampus E4_young E4/E4 Wild-type 3 months
SA245384JJ3_76_HypothalamusHypothalamus E3_FAD E3/E3 Hemizygous 12 months
SA245385JJ3_73_HypothalamusHypothalamus E3_FAD E3/E3 Hemizygous 12 months
SA245386JJ3_66_HypothalamusHypothalamus E3_FAD E3/E3 Hemizygous 12 months
SA245387B425_HypothalamusHypothalamus E3_old E3/E3 Wild-type 24 months
SA245388B354_HypothalamusHypothalamus E3_old E3/E3 Wild-type 24 months
SA245389B427_HypothalamusHypothalamus E3_old E3/E3 Wild-type 24 months
SA245390B647_HypothalamusHypothalamus E3_young E3/E3 Wild-type 3 months
SA245391B648_HypothalamusHypothalamus E3_young E3/E3 Wild-type 3 months
SA245392B652_HypothalamusHypothalamus E3_young E3/E3 Wild-type 3 months
SA245393KK4_116_HypothalamusHypothalamus E4_FAD E4/E4 Hemizygous 12 months
SA245394KK4_96_HypothalamusHypothalamus E4_FAD E4/E4 Hemizygous 12 months
SA245395KK4_40_HypothalamusHypothalamus E4_FAD E4/E4 Hemizygous 12 months
SA245396C384_HypothalamusHypothalamus E4_old E4/E4 Wild-type 24 months
SA245397C202_HypothalamusHypothalamus E4_old E4/E4 Wild-type 24 months
SA245398C362_HypothalamusHypothalamus E4_old E4/E4 Wild-type 24 months
SA245399C763_HypothalamusHypothalamus E4_young E4/E4 Wild-type 3 months
SA245400C761_HypothalamusHypothalamus E4_young E4/E4 Wild-type 3 months
SA245401C762_HypothalamusHypothalamus E4_young E4/E4 Wild-type 3 months
SA245402JJ3_73_Iso CortexIso Cortex E3_FAD E3/E3 Hemizygous 12 months
SA245403JJ3_76_Iso CortexIso Cortex E3_FAD E3/E3 Hemizygous 12 months
SA245404JJ3_66_Iso CortexIso Cortex E3_FAD E3/E3 Hemizygous 12 months
SA245405B427_Iso CortexIso Cortex E3_old E3/E3 Wild-type 24 months
SA245406B425_Iso CortexIso Cortex E3_old E3/E3 Wild-type 24 months
SA245407B354_Iso CortexIso Cortex E3_old E3/E3 Wild-type 24 months
SA245408B647_Iso CortexIso Cortex E3_young E3/E3 Wild-type 3 months
SA245409B652_Iso CortexIso Cortex E3_young E3/E3 Wild-type 3 months
SA245410B648_Iso CortexIso Cortex E3_young E3/E3 Wild-type 3 months
SA245411KK4_96_Iso CortexIso Cortex E4_FAD E4/E4 Hemizygous 12 months
Showing page 1 of 2     Results:    1  2  Next     Showing results 1 to 100 of 162

Collection:

Collection ID:CO002535
Collection Summary:Three different mice for each experimental group (18 mice in total) were anesthetized via 5.0% isoflurane before exsanguination and transcardial perfusion with ice-cold Dulbecco’s phosphate buffered saline (DPBS; Gibco # 14040133). Following perfusion, hemibrains were quickly removed, leaving behind brainstem and cerebellum. Hemibrains were immediately placed in OCT compound (Fisher HealthCare Tissue Plus O.C.T. Compound Clear 4585) and gently lowered into isopentane (Sigma-Aldrich 2- Methylbutane M32631) in a beaker surrounded by dry ice (isopentane chilled to approximately -70°C). Hemibrains were submerged for 60 seconds, placed on dry ice, wrapped in aluminum foil, and stored at -80°C until sectioning.
Sample Type:Brain

Treatment:

Treatment ID:TR002554
Treatment Summary:All mice were group housed in sterile micro-isolator cages (Lab Products, Maywood, NJ), and fed autoclaved food and acidified water ad libitum. No additional treatment was applied, with the only comparisons being across different genotypes and ages as specified in the study design table.

Sample Preparation:

Sampleprep ID:SP002548
Sampleprep Summary:Prepared brain hemispheres were cryosectioned to 10 μm thick coronal sections at approximately Bregma -2.00 mm. Brain sections were mounted on glass slides and prepared for MALDI MSI as follows: After desiccation for one hour, slides were sprayed with 14 passes of 7mg/mL N-(1-Naphthyl) ethylenediamine dihydrochloride (NEDC) matrix (Sigma) in 70% methanol (HPLC-grade, Sigma) which was applied at 0.06mL/min with a 3mm offset and a velocity of 1200mm/min at 30°C and 10psi using the M5 Sprayer with a heated tray of 50°C. Slides were used immediately or stored in a desiccator until analysis.

Combined analysis:

Analysis ID AN004002
Analysis type MS
Chromatography type None (Direct infusion)
Chromatography system none
Column none
MS Type MALDI
MS instrument type QTOF
MS instrument name Waters Synapt G2 XS QTOF
Ion Mode NEGATIVE
Units Intensity per pixel

Chromatography:

Chromatography ID:CH002955
Chromatography Summary:Not applicable (MALDI MSI)
Instrument Name:none
Column Name:none
Column Temperature:N/A
Flow Gradient:N/A
Flow Rate:N/A
Solvent A:N/A
Solvent B:N/A
Chromatography Type:None (Direct infusion)

MS:

MS ID:MS003750
Analysis ID:AN004002
Instrument Name:Waters Synapt G2 XS QTOF
Instrument Type:QTOF
MS Type:MALDI
MS Comments:For the detection of lipids, a Waters SynaptG2-Xs high-definition mass spectrometer equipped with traveling wave ion mobility was employed with the following parameters. The laser was operating at 2000 Hz with an energy of 300 AU and spot size of 50 μm at X and Y coordinates of 100μm with mass range set at 50 – 1000 m/z in negative mode. MALDI-MSI data files were processed to adjust for mass drift during the MALDI scan and to enhance image quality and improve signal-tonoise ratio using an algorithm available within the High-Definition Imaging (HDI) software (Waters Corp). To adjust for mass drift during the MALDI scan, raw files were processed using a carefully curated list of 20 MALDI NEDC matrix peaks (m/z), 26 small molecule MALDI peaks(m/z), and 24 lipid peaks(m/z). Files were processed at a sample duration of 10 sec at a frequency rate of 0.5 min, and an m/z window of 0.1 Da, using an internal lock mass of previously defined metabolite of taurine 124.007 m/z with a tolerance of 1amu and a minimum signal intensity of 100,000 counts. Data acquisition spectrums were uploaded to the HDI software for the generation of lipid images. Regions of interest (ROIs) were user defined by a blinded investigator using anatomical reference points based on the mouse Allen Brain atlas. For all pixels defined within a ROI, peak intensities were averaged and normalized by total ion current (TIC) and number of pixels.
Ion Mode:NEGATIVE
  logo