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MetaboLights MTBLS495 - GNPS Absolute quantitative lipidomics reveals lipidome-wide alterations in aging brain (Mouse brain NEG UPLC-MS assay)

ABSTRACT: INTRODUCTION: The absolute quantitation of lipids at the lipidome-wide scale is a challenge but plays an important role in the comprehensive study of lipid metabolism.
OBJECTIVES: We aim to develop a high-throughput quantitative lipidomics approach to enable the simultaneous identification and absolute quantification of hundreds of lipids in a single experiment. Then, we will systematically characterize lipidome-wide changes in the aging mouse brain and provide a link between aging and disordered lipid homeostasis.
METHODS: We created an in-house lipid spectral library, containing 76,361 lipids and 181,300 MS/MS spectra in total, to support accurate lipid identification. Then, we developed a response factor-based approach for the large-scale absolute quantifications of lipids.
RESULTS: Using the lipidomics approach, we absolutely quantified 1212 and 864 lipids in human cells and mouse brains, respectively. The quantification accuracy was validated using the traditional approach with a median relative error of 12.6%. We further characterized the lipidome-wide changes in aging mouse brains, and dramatic changes were observed in both glycerophospholipids and sphingolipids. Sphingolipids with longer acyl chains tend to accumulate in aging brains. Membrane-esterified fatty acids demonstrated diverse changes with aging, while most polyunsaturated fatty acids consistently decreased.
CONCLUSION: We developed a high-throughput quantitative lipidomics approach and systematically characterized the lipidome-wide changes in aging mouse brains. The results proved a link between aging and disordered lipid homeostasis.

Mouse brain NEG UPLC-MS assay data is reported in the current study MTBLS495.
Mouse brain POS UPLC-MS assay data associated to this study is reported in MTBLS562.

Linked Studies: MTBLS562

INSTRUMENT(S): TripleTOF 5600+|1002584

ORGANISM(S): Mus Musculus|10090

SUBMITTER: Zhu Zheng-Jiang

PROVIDER: MSV000085749 | GNPS | Tue Jul 14 14:09:00 BST 2020

REPOSITORIES: GNPS

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Project description:INTRODUCTION: The absolute quantitation of lipids at the lipidome-wide scale is a challenge but plays an important role in the comprehensive study of lipid metabolism. OBJECTIVES: We aim to develop a high-throughput quantitative lipidomics approach to enable the simultaneous identification and absolute quantification of hundreds of lipids in a single experiment. Then, we will systematically characterize lipidome-wide changes in the aging mouse brain and provide a link between aging and disordered lipid homeostasis. METHODS: We created an in-house lipid spectral library, containing 76,361 lipids and 181,300 MS/MS spectra in total, to support accurate lipid identification. Then, we developed a response factor-based approach for the large-scale absolute quantifications of lipids. RESULTS: Using the lipidomics approach, we absolutely quantified 1212 and 864 lipids in human cells and mouse brains, respectively. The quantification accuracy was validated using the traditional approach with a median relative error of 12.6%. We further characterized the lipidome-wide changes in aging mouse brains, and dramatic changes were observed in both glycerophospholipids and sphingolipids. Sphingolipids with longer acyl chains tend to accumulate in aging brains. Membrane-esterified fatty acids demonstrated diverse changes with aging, while most polyunsaturated fatty acids consistently decreased. CONCLUSION: We developed a high-throughput quantitative lipidomics approach and systematically characterized the lipidome-wide changes in aging mouse brains. The results proved a link between aging and disordered lipid homeostasis. Mouse brain POS UPLC-MS assay data is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS562' rel='noopener noreferrer' target='_blank'>MTBLS562</a>. Mouse brain NEG UPLC-MS assay data associated to this study is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS495' rel='noopener noreferrer' target='_blank'>MTBLS495</a>.

Project description:INTRODUCTION: The absolute quantitation of lipids at the lipidome-wide scale is a challenge but plays an important role in the comprehensive study of lipid metabolism. OBJECTIVES: We aim to develop a high-throughput quantitative lipidomics approach to enable the simultaneous identification and absolute quantification of hundreds of lipids in a single experiment. Then, we will systematically characterize lipidome-wide changes in the aging mouse brain and provide a link between aging and disordered lipid homeostasis. METHODS: We created an in-house lipid spectral library, containing 76,361 lipids and 181,300 MS/MS spectra in total, to support accurate lipid identification. Then, we developed a response factor-based approach for the large-scale absolute quantifications of lipids. RESULTS: Using the lipidomics approach, we absolutely quantified 1212 and 864 lipids in human cells and mouse brains, respectively. The quantification accuracy was validated using the traditional approach with a median relative error of 12.6%. We further characterized the lipidome-wide changes in aging mouse brains, and dramatic changes were observed in both glycerophospholipids and sphingolipids. Sphingolipids with longer acyl chains tend to accumulate in aging brains. Membrane-esterified fatty acids demonstrated diverse changes with aging, while most polyunsaturated fatty acids consistently decreased. CONCLUSION: We developed a high-throughput quantitative lipidomics approach and systematically characterized the lipidome-wide changes in aging mouse brains. The results proved a link between aging and disordered lipid homeostasis. Mouse brain NEG UPLC-MS assay data is reported in the current study <a href='https://www.ebi.ac.uk/metabolights/MTBLS495' rel='noopener noreferrer' target='_blank'>MTBLS495</a>.Mouse brain POS UPLC-MS assay data associated to this study is reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS562' rel='noopener noreferrer' target='_blank'>MTBLS562</a>.

Project description:Background: The risk for dementia increases exponentially from the seventh decade of life. Identifying and understanding the biochemical changes that sensitize the ageing brain to neurodegeneration will provide new opportunities for dementia prevention and treatment. This study aimed to determine how ageing and major genetic risk factors for dementia affect the hippocampal proteome and lipidome of neurologically-normal humans over the age of 65. The hippocampus was chosen as it is highly susceptible to atrophy with ageing and in several neurodegenerative diseases. Methods: Mass spectrometry-based proteomic and lipidomic analysis of CA1 hippocampus samples from 74 neurologically normal human donors, aged 66 – 104, was used in combination with multiple regression models and gene set enrichment analysis to identify age-dependent changes in the proteome and lipidome. ANOVA was used to test the effect of major dementia risk alleles in the TMEM106B and APOE genes on the hippocampal proteome and lipidome, adjusting for age, gender, and post-mortem interval. Fibrillar C-terminal TMEM106B fragments were isolated using sarkosyl fractionation and quantified by immunoblotting. Results: Forty proteins were associated with age at false discovery rate-corrected P<0.05, including proteins that regulate cell adhesion, the cytoskeleton, amino acid and lipid metabolism, and ribosomal subunits. TMEM106B, a regulator of lysosomal and oligodendrocyte function, was regulated with greatest effect size. The increase in TMEM106B levels with ageing was specific to carriers of the rs1990622-A allele in the TMEM106B gene that increases risk for frontotemporal dementia, Alzheimer’s disease, Parkinson’s disease, and hippocampal sclerosis with ageing. Rs1990622-A was also associated with higher TMEM106B fibril content. Hippocampal lipids were not significantly affected by APOE genotype, however levels of myelin-enriched sulfatides and hexosylceramides were significantly lower, and polyunsaturated phospholipids were higher, in rs1990622-A carriers after controlling for APOE genotype. Conclusions: Our study demonstrates that TMEM106B protein abundance is increased with brain ageing in humans, establishes that dementia risk allele rs1990622-A predisposes to TMEM106B fibril formation in the hippocampus, and provides the first evidence that rs1990622-A affects brain lipid homeostasis, particularly myelin lipids. Our data suggests that TMEM106B is one of a growing list of major dementia risk genes that affect glial lipid metabolism.

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MetaboLights MTBLS495 - GNPS Absolute quantitative lipidomics reveals lipidome-wide alterations in aging brain (Mouse brain NEG UPLC-MS assay)

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