Inflammatory Pathways Are Impaired in Alzheimer Disease and Differentially Associated With Apolipoprotein E Status

Courtney M. Kloske; Adam J. Dugan; Erica M. Weekman; Zachary Winder; Ela Patel; Peter T. Nelson; David W. Fardo; Donna M. Wilcock

doi:10.1093/jnen/nlab085

Inflammatory Pathways Are Impaired in Alzheimer Disease and Differentially Associated With Apolipoprotein E Status

Courtney M. Kloske, Adam J. Dugan, Erica M. Weekman, Zachary Winder, Ela Patel, Peter T. Nelson, David W. Fardo, Donna M. Wilcock

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

10 Scopus citations

Abstract

Alzheimer disease (AD) is a neurodegenerative disease characterized by a cognitive decline leading to dementia. The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-e4 significantly increases AD risk, APOE-e3 is the most common gene variant, and APOE-e2 protects against AD. However, the underlying mechanisms of APOE-e4 on AD risk remains unclear, with APOEe4 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-e3/3 (n 9) or APOE-e4/4 (n 10) participants with AD pathology and APOE-e3/3 (n 9) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-e4/4-AD individuals compared to APOE-e3/3- AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-e3 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-e4 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology.

Original language	English
Pages (from-to)	922-932
Number of pages	11
Journal	Journal of Neuropathology and Experimental Neurology
Volume	80
Issue number	10
DOIs	https://doi.org/10.1093/jnen/nlab085
State	Published - Oct 1 2021

Bibliographical note

Funding Information:
Research reported in this article was funded by grants P30-AG028383 (UK-ADRC), 1RF1AG057754-01 (DMW), 1T32AG057461-01 (CMK), and 1F31AG069372-01 (CMK) from the National Institute on Aging. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2021 Oxford University Press. All rights reserved.

Keywords

Alzheimer disease
Apolipoprotein E
Microglia
NanoString
Neuroinflammation
Neuropathology

ASJC Scopus subject areas

Medicine (all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/jnen/nlab085

Cite this

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title = "Inflammatory Pathways Are Impaired in Alzheimer Disease and Differentially Associated With Apolipoprotein E Status",

abstract = "Alzheimer disease (AD) is a neurodegenerative disease characterized by a cognitive decline leading to dementia. The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-e4 significantly increases AD risk, APOE-e3 is the most common gene variant, and APOE-e2 protects against AD. However, the underlying mechanisms of APOE-e4 on AD risk remains unclear, with APOEe4 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-e3/3 (n 9) or APOE-e4/4 (n 10) participants with AD pathology and APOE-e3/3 (n 9) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-e4/4-AD individuals compared to APOE-e3/3- AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-e3 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-e4 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology.",

keywords = "Alzheimer disease, Apolipoprotein E, Microglia, NanoString, Neuroinflammation, Neuropathology",

author = "Kloske, {Courtney M.} and Dugan, {Adam J.} and Weekman, {Erica M.} and Zachary Winder and Ela Patel and Nelson, {Peter T.} and Fardo, {David W.} and Wilcock, {Donna M.}",

note = "Funding Information: Research reported in this article was funded by grants P30-AG028383 (UK-ADRC), 1RF1AG057754-01 (DMW), 1T32AG057461-01 (CMK), and 1F31AG069372-01 (CMK) from the National Institute on Aging. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2021 Oxford University Press. All rights reserved.",

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AU - Dugan, Adam J.

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AU - Winder, Zachary

AU - Patel, Ela

AU - Nelson, Peter T.

AU - Fardo, David W.

AU - Wilcock, Donna M.

N1 - Funding Information: Research reported in this article was funded by grants P30-AG028383 (UK-ADRC), 1RF1AG057754-01 (DMW), 1T32AG057461-01 (CMK), and 1F31AG069372-01 (CMK) from the National Institute on Aging. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2021 Oxford University Press. All rights reserved.

PY - 2021/10/1

Y1 - 2021/10/1

N2 - Alzheimer disease (AD) is a neurodegenerative disease characterized by a cognitive decline leading to dementia. The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-e4 significantly increases AD risk, APOE-e3 is the most common gene variant, and APOE-e2 protects against AD. However, the underlying mechanisms of APOE-e4 on AD risk remains unclear, with APOEe4 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-e3/3 (n 9) or APOE-e4/4 (n 10) participants with AD pathology and APOE-e3/3 (n 9) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-e4/4-AD individuals compared to APOE-e3/3- AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-e3 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-e4 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology.

AB - Alzheimer disease (AD) is a neurodegenerative disease characterized by a cognitive decline leading to dementia. The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-e4 significantly increases AD risk, APOE-e3 is the most common gene variant, and APOE-e2 protects against AD. However, the underlying mechanisms of APOE-e4 on AD risk remains unclear, with APOEe4 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-e3/3 (n 9) or APOE-e4/4 (n 10) participants with AD pathology and APOE-e3/3 (n 9) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-e4/4-AD individuals compared to APOE-e3/3- AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-e3 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-e4 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology.

KW - Alzheimer disease

KW - Apolipoprotein E

KW - Microglia

KW - NanoString

KW - Neuroinflammation

KW - Neuropathology

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U2 - 10.1093/jnen/nlab085

DO - 10.1093/jnen/nlab085

M3 - Article

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AN - SCOPUS:85123226566

SN - 0022-3069

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JO - Journal of Neuropathology and Experimental Neurology

JF - Journal of Neuropathology and Experimental Neurology

IS - 10

ER -

Inflammatory Pathways Are Impaired in Alzheimer Disease and Differentially Associated With Apolipoprotein E Status

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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