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APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge [scRNA-seq 1]

ABSTRACT: 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 Hif1a 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE212317 | GEO | 2022/09/04

REPOSITORIES: GEO

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APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge [Spatial transcriptomics]

Project description: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 Hif1a 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.

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APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge [Bulk RNA-seq]

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APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge (Part 1 of 3)

Project description: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.

2022-09-20 | ST002450 | MetabolomicsWorkbench

APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge (Part 2 of 3)

Project description: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.

2023-01-20 | ST002451 | MetabolomicsWorkbench

APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge (Part 3 of 3)

Project description: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.

2022-11-14 | ST002453 | MetabolomicsWorkbench

APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes (bulk RNA-Seq)

Project description:Apolipoprotein 4 (APOE4), is the strongest genetic risk allele associated with the development of late onset Alzheimer’s disease (AD). Across the CNS, astrocytes are the predominant expressor of Apoe while also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional neuro-immunometabolism, however insights into the molecular constituents driving these responses remain unclear. Utilizing complimentary approaches across humanized ApoE expressing mice and isogenic IPS astrocytes, we demonstrate that harboring ApoE4 alters astrocyte immunometabolic response to pro-inflammatory stimuli. Our findings demonstrate that ApoE4-expressing astrocytes acquire distinct transcriptional repertoires at the single-cell and spatially-resolved domains, which driven, in-part, by preferential utilization of the cRel transcription factor. Further, inhibiting cRel translocation abrogated inflammatory-induced glycolytic shift and ultimately resulted in significantly dampened glycolysis-associated metabolites in tandem with mitigating production of multiple pro-inflammatory cytokines. Altogether, our findings elucidate novel cellular underpinnings by which ApoE4 drives maladaptive immunometabolic responses of astrocytes.

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Project description:In recent years, it has been recognized the central role of cell bioenergetics in regulating immune cell function and fate giving rise to the interest in immunometabolism, an area of research focused on the interaction between metabolic regulation and immune function. Immunometabolism has been studied in the modulation of macrophage polarization. Thus, early metabolic changes associated with the polarisation of macrophages into pro-inflammatory or pro-resolving cells under different stimuli have been characterized. Tumour-associated macrophages are among the most abundant cells in the tumour microenvironment; however, it exists an unmet need to study the effect of chemotherapeutics on macrophage immunometabolism. Here, a systems biology approach that integrates transcriptomics and metabolomics unveils the immunometabolic effects of trabectedin (TRB) and lurbinectedin (LUR), two intercalating DNA agents with proved antitumor activity in the low nanomolar range. Our results show that TRB and LUR activate human macrophages towards a pro-inflammatory functional phenotype by inducing a specific metabolic rewiring program that includes ROS production and changes in the mitochondrial inner membrane potential, increased pentose phosphate pathway, TCA cycle serine and methylglyoxal pathways in human macrophages. glutamine, aspartate, histidine, and proline consumption are increased whereas 50 nM TRB increases lactate release and oxygen consumption is depressed . The observed immunometabolic rewiring could explain additional antitumor activities of these compounds and open new avenues to design therapeutic interventions that specifically target the immunometabolic landscape in the treatment of cancer.

2023-06-25 | GSE235390 | GEO

Integrated approach reveals diet, APOE genotype and sex affect immune response in APP mice

Project description:Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that is influenced by genetic and environmental risk factors, such as inheritance of ε4 allele of APOE (APOE4), sex and diet. Here, we examined the effect of high fat diet (HFD) on amyloid pathology and expression profile in brains of AD model mice expressing human APOE isoforms (APP/E3 and APP/E4 mice). APP/E3 and APP/E4 mice were fed HFD or Normal diet for 3 months. We found that HFD significantly increased amyloid plaques in male and female APP/E4, but not in APP/E3 mice. To identify differentially expressed genes and gene-networks correlated to diet, APOE isoform and sex, we performed RNA sequencing and applied Weighted Gene Co-expression Network Analysis. We determined that the immune response network with major hubs Tyrobp/DAP12, Csf1r, Tlr2, C1qc and Laptm5 correlated significantly and positively to the phenotype of female APP/E4-HFD mice. Correspondingly, we found that in female APP/E4-HFD mice, microglia coverage around plaques, particularly of larger size, was significantly reduced. This suggests altered containment of the plaque growth and sex-dependent vulnerability in response to diet. The results of our study show concurrent impact of diet, APOE isoform and sex on the brain transcriptome and AD-like phenotype.

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