APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

Sangderk Lee; Nicholas A. Devanney; Lesley R. Golden; Cathryn T. Smith; James L. Schwartz; Adeline E. Walsh; Harrison A. Clarke; Danielle S. Goulding; Elizabeth J. Allenger; Gabriella Morillo-Segovia; Cassi M. Friday; Amy A. Gorman; Tara R. Hawkinson; Steven M. MacLean; Holden C. Williams; Ramon C. Sun; Josh M. Morganti; Lance A. Johnson

doi:10.1016/j.celrep.2023.112196

APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

Sangderk Lee, Nicholas A. Devanney, Lesley R. Golden, Cathryn T. Smith, James L. Schwartz, Adeline E. Walsh, Harrison A. Clarke, Danielle S. Goulding, Elizabeth J. Allenger, Gabriella Morillo-Segovia, Cassi M. Friday, Amy A. Gorman, Tara R. Hawkinson, Steven M. MacLean, Holden C. Williams, Ramon C. Sun, Josh M. Morganti, Lance A. Johnson

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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 in mice expressing human APOE to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNA sequencing (RNA-seq) 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 and a disrupted tricarboxylic acid (TCA) cycle and are inherently pro-glycolytic, while spatial transcriptomics and 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 and provide valuable, interactive resources for discovery and validation research.

Original language	English
Article number	112196
Journal	Cell Reports
Volume	42
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2023.112196
State	Published - Mar 28 2023

Bibliographical note

Funding Information:
We thank Dr. Doug Harrison and Jim Begley at the University of Kentucky Arts & Sciences Imaging Center for their invaluable assistance with scRNA-seq and ST analyses. We also thank Dr. Matthew Gentry for his continued support and guidance. Finally, we thank Dr. Tomoko Sengoku and Michael Alstott at the University of Kentucky Redox Metabolism Shared Resource Facility, supported by NCI Cancer Center Support Grant (P30 CA177558), for their assistance with the Seahorse assays. This work was supported by the National Institute on Aging (R01AG060056, R01AG062550, and R01AG080589 to L.A.J.; R01AG070830 and RF1NS118558 to J.M.M.; R01AG066653 to R.C.S.; F31AG076282, T32AG057461, and T32GM118292 to N.A.D.; R01AG062550-03S1 to C.M.F.), American Cancer Society Institutional Research (grant 16-182-28 to R.C.S.), St. Baldrick's Foundation (R.C.S.), Cure Alzheimer's Fund (L.A.J. R.C.S. and J.M.M.), and the Alzheimer's Association (L.A.J.). L.A.J. and J.M.M. designed the experiments. S.L. N.A.D. J.M.M. and L.A.J. analyzed the data and wrote the paper. N.A.D. completed the metabolic analyses of microglia, including metabolomics, Seahorse assays, and RT-PCR. E.J.A. and J.L.S. performed tissue preparation, sectioning, and staining for ST and immunohistochemistry, respectively. C.T.S. C.M.F. A.E.W. G.M.-S. S.M.M. and H.C.W. assisted with bulk and scRNA-seq analyses. J.M.M. and L.A.J. supervised scRNA-seq and ST workflows, with technical assistance from J.L.S. A.A.G. and D.S.G. R.C.S. oversaw MALDI MSI, with technical and analytical assistance from L.R.G. H.A.C. and T.R.H. All authors read the paper and provided edits. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. One or more of the authors of this paper self-identifies as a gender minority in their field of research. One or more of the authors of this paper self-identifies as a member of the LGBTQIA+ community. One or more of the authors of this paper received support from a program designed to increase minority representation in their field of research.

Funding Information:
We thank Dr. Doug Harrison and Jim Begley at the University of Kentucky Arts & Sciences Imaging Center for their invaluable assistance with scRNA-seq and ST analyses. We also thank Dr. Matthew Gentry for his continued support and guidance. Finally, we thank Dr. Tomoko Sengoku and Michael Alstott at the University of Kentucky Redox Metabolism Shared Resource Facility, supported by NCI Cancer Center Support Grant ( P30 CA177558 ), for their assistance with the Seahorse assays. This work was supported by the National Institute on Aging ( R01AG060056 , R01AG062550 , and R01AG080589 to L.A.J.; R01AG070830 and RF1NS118558 to J.M.M.; R01AG066653 to R.C.S.; F31AG076282 , T32AG057461 , and T32GM118292 to N.A.D.; R01AG062550-03S1 to C.M.F.), American Cancer Society Institutional Research (grant 16-182-28 to R.C.S.), St. Baldrick’s Foundation (R.C.S.), Cure Alzheimer’s Fund (L.A.J., R.C.S., and J.M.M.), and the Alzheimer's Association (L.A.J.).

Publisher Copyright:
© 2023 The Author(s)

Keywords

APOE
Apolipoprotein E
CP: Neuroscience
DAM
LPS
aging
amyloid
immunometabolism
microglia
scRNA-seq
spatial transcriptomics

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (all)

Access to Document

10.1016/j.celrep.2023.112196

Cite this

Lee, S., Devanney, N. A., Golden, L. R., Smith, C. T., Schwartz, J. L., Walsh, A. E., Clarke, H. A., Goulding, D. S., Allenger, E. J., Morillo-Segovia, G., Friday, C. M., Gorman, A. A., Hawkinson, T. R., MacLean, S. M., Williams, H. C., Sun, R. C., Morganti, J. M., & Johnson, L. A. (2023). APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge. Cell Reports, 42(3), Article 112196. https://doi.org/10.1016/j.celrep.2023.112196

@article{a00b878840844e4086bc0de01e65f7e6,

title = "APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge",

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 in mice expressing human APOE to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNA sequencing (RNA-seq) 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 and a disrupted tricarboxylic acid (TCA) cycle and are inherently pro-glycolytic, while spatial transcriptomics and 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 and provide valuable, interactive resources for discovery and validation research.",

keywords = "APOE, Apolipoprotein E, CP: Neuroscience, DAM, LPS, aging, amyloid, immunometabolism, microglia, scRNA-seq, spatial transcriptomics",

author = "Sangderk Lee and Devanney, {Nicholas A.} and Golden, {Lesley R.} and Smith, {Cathryn T.} and Schwartz, {James L.} and Walsh, {Adeline E.} and Clarke, {Harrison A.} and Goulding, {Danielle S.} and Allenger, {Elizabeth J.} and Gabriella Morillo-Segovia and Friday, {Cassi M.} and Gorman, {Amy A.} and Hawkinson, {Tara R.} and MacLean, {Steven M.} and Williams, {Holden C.} and Sun, {Ramon C.} and Morganti, {Josh M.} and Johnson, {Lance A.}",

note = "Funding Information: We thank Dr. Doug Harrison and Jim Begley at the University of Kentucky Arts & Sciences Imaging Center for their invaluable assistance with scRNA-seq and ST analyses. We also thank Dr. Matthew Gentry for his continued support and guidance. Finally, we thank Dr. Tomoko Sengoku and Michael Alstott at the University of Kentucky Redox Metabolism Shared Resource Facility, supported by NCI Cancer Center Support Grant (P30 CA177558), for their assistance with the Seahorse assays. This work was supported by the National Institute on Aging (R01AG060056, R01AG062550, and R01AG080589 to L.A.J.; R01AG070830 and RF1NS118558 to J.M.M.; R01AG066653 to R.C.S.; F31AG076282, T32AG057461, and T32GM118292 to N.A.D.; R01AG062550-03S1 to C.M.F.), American Cancer Society Institutional Research (grant 16-182-28 to R.C.S.), St. Baldrick's Foundation (R.C.S.), Cure Alzheimer's Fund (L.A.J. R.C.S. and J.M.M.), and the Alzheimer's Association (L.A.J.). L.A.J. and J.M.M. designed the experiments. S.L. N.A.D. J.M.M. and L.A.J. analyzed the data and wrote the paper. N.A.D. completed the metabolic analyses of microglia, including metabolomics, Seahorse assays, and RT-PCR. E.J.A. and J.L.S. performed tissue preparation, sectioning, and staining for ST and immunohistochemistry, respectively. C.T.S. C.M.F. A.E.W. G.M.-S. S.M.M. and H.C.W. assisted with bulk and scRNA-seq analyses. J.M.M. and L.A.J. supervised scRNA-seq and ST workflows, with technical assistance from J.L.S. A.A.G. and D.S.G. R.C.S. oversaw MALDI MSI, with technical and analytical assistance from L.R.G. H.A.C. and T.R.H. All authors read the paper and provided edits. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. One or more of the authors of this paper self-identifies as a gender minority in their field of research. One or more of the authors of this paper self-identifies as a member of the LGBTQIA+ community. One or more of the authors of this paper received support from a program designed to increase minority representation in their field of research. Funding Information: We thank Dr. Doug Harrison and Jim Begley at the University of Kentucky Arts & Sciences Imaging Center for their invaluable assistance with scRNA-seq and ST analyses. We also thank Dr. Matthew Gentry for his continued support and guidance. Finally, we thank Dr. Tomoko Sengoku and Michael Alstott at the University of Kentucky Redox Metabolism Shared Resource Facility, supported by NCI Cancer Center Support Grant ( P30 CA177558 ), for their assistance with the Seahorse assays. This work was supported by the National Institute on Aging ( R01AG060056 , R01AG062550 , and R01AG080589 to L.A.J.; R01AG070830 and RF1NS118558 to J.M.M.; R01AG066653 to R.C.S.; F31AG076282 , T32AG057461 , and T32GM118292 to N.A.D.; R01AG062550-03S1 to C.M.F.), American Cancer Society Institutional Research (grant 16-182-28 to R.C.S.), St. Baldrick{\textquoteright}s Foundation (R.C.S.), Cure Alzheimer{\textquoteright}s Fund (L.A.J., R.C.S., and J.M.M.), and the Alzheimer's Association (L.A.J.). Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = mar,

day = "28",

doi = "10.1016/j.celrep.2023.112196",

language = "English",

volume = "42",

number = "3",

}

Lee, S, Devanney, NA, Golden, LR, Smith, CT, Schwartz, JL, Walsh, AE, Clarke, HA, Goulding, DS, Allenger, EJ, Morillo-Segovia, G, Friday, CM, Gorman, AA, Hawkinson, TR, MacLean, SM, Williams, HC, Sun, RC, Morganti, JM & Johnson, LA 2023, 'APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge', Cell Reports, vol. 42, no. 3, 112196. https://doi.org/10.1016/j.celrep.2023.112196

TY - JOUR

T1 - APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

AU - Lee, Sangderk

AU - Devanney, Nicholas A.

AU - Golden, Lesley R.

AU - Smith, Cathryn T.

AU - Schwartz, James L.

AU - Walsh, Adeline E.

AU - Clarke, Harrison A.

AU - Goulding, Danielle S.

AU - Allenger, Elizabeth J.

AU - Morillo-Segovia, Gabriella

AU - Friday, Cassi M.

AU - Gorman, Amy A.

AU - Hawkinson, Tara R.

AU - MacLean, Steven M.

AU - Williams, Holden C.

AU - Sun, Ramon C.

AU - Morganti, Josh M.

AU - Johnson, Lance A.

N1 - Funding Information: We thank Dr. Doug Harrison and Jim Begley at the University of Kentucky Arts & Sciences Imaging Center for their invaluable assistance with scRNA-seq and ST analyses. We also thank Dr. Matthew Gentry for his continued support and guidance. Finally, we thank Dr. Tomoko Sengoku and Michael Alstott at the University of Kentucky Redox Metabolism Shared Resource Facility, supported by NCI Cancer Center Support Grant (P30 CA177558), for their assistance with the Seahorse assays. This work was supported by the National Institute on Aging (R01AG060056, R01AG062550, and R01AG080589 to L.A.J.; R01AG070830 and RF1NS118558 to J.M.M.; R01AG066653 to R.C.S.; F31AG076282, T32AG057461, and T32GM118292 to N.A.D.; R01AG062550-03S1 to C.M.F.), American Cancer Society Institutional Research (grant 16-182-28 to R.C.S.), St. Baldrick's Foundation (R.C.S.), Cure Alzheimer's Fund (L.A.J. R.C.S. and J.M.M.), and the Alzheimer's Association (L.A.J.). L.A.J. and J.M.M. designed the experiments. S.L. N.A.D. J.M.M. and L.A.J. analyzed the data and wrote the paper. N.A.D. completed the metabolic analyses of microglia, including metabolomics, Seahorse assays, and RT-PCR. E.J.A. and J.L.S. performed tissue preparation, sectioning, and staining for ST and immunohistochemistry, respectively. C.T.S. C.M.F. A.E.W. G.M.-S. S.M.M. and H.C.W. assisted with bulk and scRNA-seq analyses. J.M.M. and L.A.J. supervised scRNA-seq and ST workflows, with technical assistance from J.L.S. A.A.G. and D.S.G. R.C.S. oversaw MALDI MSI, with technical and analytical assistance from L.R.G. H.A.C. and T.R.H. All authors read the paper and provided edits. The authors declare no competing interests. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. One or more of the authors of this paper self-identifies as a gender minority in their field of research. One or more of the authors of this paper self-identifies as a member of the LGBTQIA+ community. One or more of the authors of this paper received support from a program designed to increase minority representation in their field of research. Funding Information: We thank Dr. Doug Harrison and Jim Begley at the University of Kentucky Arts & Sciences Imaging Center for their invaluable assistance with scRNA-seq and ST analyses. We also thank Dr. Matthew Gentry for his continued support and guidance. Finally, we thank Dr. Tomoko Sengoku and Michael Alstott at the University of Kentucky Redox Metabolism Shared Resource Facility, supported by NCI Cancer Center Support Grant ( P30 CA177558 ), for their assistance with the Seahorse assays. This work was supported by the National Institute on Aging ( R01AG060056 , R01AG062550 , and R01AG080589 to L.A.J.; R01AG070830 and RF1NS118558 to J.M.M.; R01AG066653 to R.C.S.; F31AG076282 , T32AG057461 , and T32GM118292 to N.A.D.; R01AG062550-03S1 to C.M.F.), American Cancer Society Institutional Research (grant 16-182-28 to R.C.S.), St. Baldrick’s Foundation (R.C.S.), Cure Alzheimer’s Fund (L.A.J., R.C.S., and J.M.M.), and the Alzheimer's Association (L.A.J.). Publisher Copyright: © 2023 The Author(s)

PY - 2023/3/28

Y1 - 2023/3/28

N2 - 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 in mice expressing human APOE to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNA sequencing (RNA-seq) 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 and a disrupted tricarboxylic acid (TCA) cycle and are inherently pro-glycolytic, while spatial transcriptomics and 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 and provide valuable, interactive resources for discovery and validation research.

AB - 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 in mice expressing human APOE to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNA sequencing (RNA-seq) 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 and a disrupted tricarboxylic acid (TCA) cycle and are inherently pro-glycolytic, while spatial transcriptomics and 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 and provide valuable, interactive resources for discovery and validation research.

KW - APOE

KW - Apolipoprotein E

KW - CP: Neuroscience

KW - DAM

KW - LPS

KW - aging

KW - amyloid

KW - immunometabolism

KW - microglia

KW - scRNA-seq

KW - spatial transcriptomics

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U2 - 10.1016/j.celrep.2023.112196

DO - 10.1016/j.celrep.2023.112196

M3 - Article

C2 - 36871219

AN - SCOPUS:85149267011

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 112196

ER -

APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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