Summary of Study ST003972
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 PR002488. The data can be accessed directly via it's Project DOI: 10.21228/M81V8V This work is supported by NIH grant, U2C- DK119886. See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Study ID | ST003972 |
| Study Title | Lipid cargo profiling of human brain-derived extracellular vesicles by APOE genotype in Alzheimer’s Disease |
| Study Summary | Objective: This study aimed to characterize the lipidomic profiles of brain-derived extracellular vesicles (BDEVs) isolated from human APOE3/3 and APOE4/4 Alzheimer's disease (AD) brains, and to evaluate how APOE4-associated lipid alterations contribute to tau pathology and neuroinflammation. Methods: Using a multidimensional mass spectrometry-based shotgun lipidomics approach, we profiled BDEVs from 40 postmortem AD brain samples (20 APOE3/3, 20 APOE4/4). Statistical and bioinformatic analyses were applied to identify significant genotype-specific lipidomic changes and their associations with key pathological and biological outcomes. Results: BDEVs from APOE4/4 brains exhibited a distinct lipidomic signature characterized by altered levels of free fatty acids, sphingolipids, cholesterol esters, and phospholipids. These changes were notably associated with increased tau accumulation and heightened neuroinflammatory markers. Among these alterations, specific lipid species demonstrated strong correlations with tau pathology and glial activation, suggesting a mechanistic link between APOE4-driven lipid remodeling and AD progression. Conclusion: Our findings uncover a novel APOE4-specific mechanism in which lipid alterations within BDEVs may drive tau propagation and neuroinflammatory responses. These results provide new insights into lipid-mediated pathways of neurodegeneration and highlight the potential for targeting lipid metabolism and extracellular vesicle pathways in APOE4-related AD. |
| Institute | Mayo Clinic |
| Last Name | Ikezu |
| First Name | Tsuneya |
| Address | 4500 San Pablo Rd S Jacksonville, FL 32224 |
| Ikezu.Tsuneya@mayo.edu | |
| Phone | 904-953-2317 |
| Submit Date | 2025-05-23 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | mzML, raw(Thermo) |
| Analysis Type Detail | MS(Dir. Inf.) |
| Release Date | 2025-07-07 |
| Release Version | 1 |
Select appropriate tab below to view additional metadata details:
Project:
| Project ID: | PR002488 |
| Project DOI: | doi: 10.21228/M81V8V |
| Project Title: | Unique lipid cargoes in APOE4 human brain-derived extracellular vesicles recruit cell adhesion molecules and promote tauopathy in Alzheimer’s disease |
| Project Type: | research |
| Project Summary: | Comprehensive analysis of brain-derived extracellular vesicles (BDEVs) isolated from human APOE3/3 and APOE4/4 Alzheimer’s disease (AD) brains using a multi-omics approach, with biological validation performed both in vivo and in vitro. |
| Institute: | Mayo Clinic |
| Last Name: | Ikezu |
| First Name: | Tsuneya |
| Address: | 4500 San Pablo Rd S Jacksonville, FL 32224 |
| Email: | Ikezu.Tsuneya@mayo.edu |
| Phone: | 904-953-2317 |
Subject:
| Subject ID: | SU004109 |
| Subject Type: | Human |
| Subject Species: | Homo sapiens |
| Taxonomy ID: | 9606 |
Factors:
Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)
| mb_sample_id | local_sample_id | Sample source | genotype |
|---|---|---|---|
| SA453309 | E3/3-18 | human brain | E3/3 |
| SA453310 | E3/3-3 | human brain | E3/3 |
| SA453311 | E3/3-25 | human brain | E3/3 |
| SA453312 | E3/3-24 | human brain | E3/3 |
| SA453313 | E3/3-23 | human brain | E3/3 |
| SA453314 | E3/3-22 | human brain | E3/3 |
| SA453315 | E3/3-21 | human brain | E3/3 |
| SA453316 | E3/3-20 | human brain | E3/3 |
| SA453317 | E3/3-19 | human brain | E3/3 |
| SA453318 | E3/3-2 | human brain | E3/3 |
| SA453319 | E3/3-17 | human brain | E3/3 |
| SA453320 | E3/3-9 | human brain | E3/3 |
| SA453321 | E3/3-15 | human brain | E3/3 |
| SA453322 | E3/3-7 | human brain | E3/3 |
| SA453323 | E3/3-8 | human brain | E3/3 |
| SA453324 | E3/3-4 | human brain | E3/3 |
| SA453325 | E3/3-11 | human brain | E3/3 |
| SA453326 | E3/3-12 | human brain | E3/3 |
| SA453327 | E3/3-13 | human brain | E3/3 |
| SA453328 | E3/3-14 | human brain | E3/3 |
| SA453329 | E4/4-14 | human brain | E4/4 |
| SA453330 | E4/4-24 | human brain | E4/4 |
| SA453331 | E4/4-22 | human brain | E4/4 |
| SA453332 | E4/4-20 | human brain | E4/4 |
| SA453333 | E4/4-19 | human brain | E4/4 |
| SA453334 | E4/4-18 | human brain | E4/4 |
| SA453335 | E4/4-17 | human brain | E4/4 |
| SA453336 | E4/4-16 | human brain | E4/4 |
| SA453337 | E4/4-15 | human brain | E4/4 |
| SA453338 | E4/4-7 | human brain | E4/4 |
| SA453339 | E4/4-13 | human brain | E4/4 |
| SA453340 | E4/4-12 | human brain | E4/4 |
| SA453341 | E4/4-10 | human brain | E4/4 |
| SA453342 | E4/4-8 | human brain | E4/4 |
| SA453343 | E4/4-6 | human brain | E4/4 |
| SA453344 | E4/4-5 | human brain | E4/4 |
| SA453345 | E4/4-4 | human brain | E4/4 |
| SA453346 | E4/4-3 | human brain | E4/4 |
| SA453347 | E4/4-2 | human brain | E4/4 |
| SA453348 | E4/4-1 | human brain | E4/4 |
| Showing results 1 to 40 of 40 |
Collection:
| Collection ID: | CO004102 |
| Collection Summary: | This study includes lipidomic profiling of BDEVs isolated from postmortem AD human brain samples. BDEVs were isolated from frozen postmortem AD brain tissues (frontal cortex) using sucrose density gradient purification and were characterized prior to analysis. A total of 40 samples were analyzed, divided into two groups: Group 1: APOE3/3 BDEVs (n = 20; 9 males and 11 females); Group 2: APOE4/4 BDEVs (n = 20; 9 males and 11 females). All samples were sex- and age-matched. Subjects ranged in age from 60 to 96 years, with a balanced distribution of male and female individuals across both groups. |
| Sample Type: | Brain |
| Storage Conditions: | -80℃ |
Treatment:
| Treatment ID: | TR004118 |
| Treatment Summary: | No specific treatment was applied; the samples carry either APOE3/3 or APOE4/4 genotypes. |
Sample Preparation:
| Sampleprep ID: | SP004115 |
| Sampleprep Summary: | BDEVs were isolated from frozen postmortem AD brain tissues (frontal cortex) using sucrose density gradient purification. BDEVs were characterized prior to analysis. Lipid species were analyzed using a multidimensional mass spectrometry-based shotgun lipidomics approach. In brief, each extracellular vesicle sample was homogenized, and the equivalent of 0.09 mg protein homogenate was added to a glass tube along with a pre-mixed lipid internal standard. Lipid extraction was performed using a modified Bligh and Dyer procedure. The lipid extract was dispersed in chloroform:methanol (1:1, v/v) at a ratio of 400 µL/mg protein for storage.And the lipid extract was further diluted to a total lipid concentration of approximately ~2 pmol/µL for shotgun lipidomics. |
Combined analysis:
| Analysis ID | AN006539 | AN006540 | AN006541 |
|---|---|---|---|
| Chromatography ID | CH004963 | CH004963 | CH004963 |
| MS ID | MS006238 | MS006239 | MS006240 |
| 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: | CH004963 |
| Instrument Name: | none |
| Column Name: | none |
| Column Temperature: | - |
| Flow Gradient: | - |
| Flow Rate: | - |
| Solvent A: | - |
| Solvent B: | - |
| Chromatography Type: | None (Direct infusion) |
MS:
| MS ID: | MS006238 |
| Analysis ID: | AN006539 |
| 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, San Jose, CA), which is equipped 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]. In shotgun lipidomics, the terms positive mode and negative mode refer to the polarity of ionization used during electrospray ionization (ESI), which directly influences the types of lipids detected and how well they are characterized. Positive ion mode generates positively charged ions and is best for detecting neutral and zwitterionic lipids, such as PC, SM, LPC, LPE, CAR, and FFA in this study. Data processing (e.g., ion peak selection, 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 and extends identification of individual molecular species through multi-dimensional mass spectrometry: development of an automated high-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., Automated lipid identification and quantification by multidimensional mass spectrometry-based shotgun lipidomics. Anal Chem, 2009. 81(11): p. 4356-68. (NOTE: Associated raw data files are PC-01~40, CAR-01~40, FFA-01~40, and CHLE-01~40) |
| Ion Mode: | POSITIVE |
| MS ID: | MS006239 |
| Analysis ID: | AN006540 |
| 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, San Jose, CA), which is equipped 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]. In shotgun lipidomics, the terms positive mode and negative mode refer to the polarity of ionization used during electrospray ionization (ESI), which directly influences the types of lipids detected and how well they are characterized. Negative ion mode generates negatively charged ions and is optimal for detecting anionic lipids, such as PE in this study. Data processing (e.g., ion peak selection, 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 and extends identification of individual molecular species through multi-dimensional mass spectrometry: development of an automated high-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., Automated lipid 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-01~40) |
| Ion Mode: | NEGATIVE |
| MS ID: | MS006240 |
| Analysis ID: | AN006541 |
| 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 is equipped 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 Q Exactive instrument for detection of CL, LCL, PS, PG and BMP detection in this study. This hybrid quadrupole-Orbitrap mass spectrometer offers high resolution, enables high-quality MS/MS fragmentation for structural analysis, and allows for detection of a broad range of lipid classes. Data processing (e.g., ion peak selection, 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 and extends identification of individual molecular species through multi-dimensional mass spectrometry: development of an automated high-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., Automated lipid identification and quantification by multidimensional mass spectrometry-based shotgun lipidomics. Anal Chem, 2009. 81(11): p. 4356-68. (NOTE: Associated raw data files are 01~40) |
| Ion Mode: | NEGATIVE |
