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Research article
Hussein Yassine
University of Southern California
Corresponding Author
ORCiD: https://orcid.org/0000-0002-2483-649X
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and risk of developing late-onset Alzheimer disease (AD), but the mechanisms for this association are not clear. Activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within plaques of the AD brain. The relation between APOE4 genotype and cPLA2 activity is not known.
Methods
Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation and activity in relation to measures of inflammation and oxidative stress.
Results
Greater cPLA2 phosphorylation and activity were identified in ApoE4 compared to ApoE3 in primary astrocytes and brains of ApoE-targeted replacement (ApoE-TR) mice. These differences were also demonstrated in brain homogenates from the inferior frontal cortex from AD patients carrying APOE3/4 compared to APOE3/3. Higher cPLA2 activation with APOE4 was associated with greater activation of the MAPK p38 pathway, as well as with higher levels of leukotriene B4 (LTB4), reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS). Inhibition of cPLA2 reduced LTB4, ROS and iNOS levels in ApoE4 primary astrocytes to those of ApoE3 astrocytes.
Conclusions
Our findings implicate greater activation of cPLA2 signaling system with APOE4, that could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.
Keywords
cPLA2, ApoE4, Alzheimer’s disease, p38, Oxidative stress
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This is a list of supplementary files associated with this preprint. Click to download.
- FigureS1.jpg
ApoE4 increases cPLA2 expression in immortalized ApoE astrocytic cultures. A, cPLA2 mRNA levels in immortalized ApoE3 and ApoE4 astrocytes. B, cPLA2 and phosphorylated cPLA2 (p-cPLA2) protein levels in immortalized ApoE3 and ApoE4 astrocytes (left) were detected by western-blot (WB).
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View the published article at Molecular Neurodegeneration.
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On 12 Jan, 2021
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On 12 Jan, 2021
Editor invited
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Version 1
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Editorial decision: Major revision
On 14 Oct, 2020
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Received 07 Oct, 2020
Review #1 received
Received 04 Oct, 2020
Reviewer #2 agreed
On 27 Sep, 2020
Reviewers invited
Invitations sent on 21 Sep, 2020
Reviewer #1 agreed
On 21 Sep, 2020
Editor assigned
On 08 Sep, 2020
First submitted
On 07 Sep, 2020
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Subject Areas
Neurobiology of Disease
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A new preprint design is coming!
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See the published version of this preprint at Molecular Neurodegeneration.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Hussein Yassine
University of Southern California
Corresponding Author
ORCiD: https://orcid.org/0000-0002-2483-649X
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Molecular Neurodegeneration.
No community comments so far
Editorial decision: Minor revision
On 10 Feb, 2021
Editor assigned
On 01 Feb, 2021
Submission checks complete
On 01 Feb, 2021
Editor invited
On 01 Feb, 2021
No comments provided
Editorial decision: Minor revision
On 21 Jan, 2021
Review #1 received
Received 19 Jan, 2021
Review #2 received
Received 17 Jan, 2021
Reviewer #2 agreed
On 13 Jan, 2021
Editor assigned
On 12 Jan, 2021
Reviewers invited
Invitations sent on 12 Jan, 2021
Reviewer #1 agreed
On 12 Jan, 2021
Submission checks complete
On 12 Jan, 2021
Editor invited
On 12 Jan, 2021
Version 1
Posted 14 Sep, 2020
No comments provided
Editorial decision: Major revision
On 14 Oct, 2020
Review #2 received
Received 07 Oct, 2020
Review #1 received
Received 04 Oct, 2020
Reviewer #2 agreed
On 27 Sep, 2020
Reviewers invited
Invitations sent on 21 Sep, 2020
Reviewer #1 agreed
On 21 Sep, 2020
Editor assigned
On 08 Sep, 2020
First submitted
On 07 Sep, 2020
Submission checks complete
On 07 Sep, 2020
Editor invited
On 07 Sep, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Neurobiology of Disease
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Molecular Neurodegeneration.
Background
Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and risk of developing late-onset Alzheimer disease (AD), but the mechanisms for this association are not clear. Activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within plaques of the AD brain. The relation between APOE4 genotype and cPLA2 activity is not known.
Methods
Mouse primary astrocytes, mouse and human brain samples differing by APOE genotypes were collected for measuring cPLA2 expression, phosphorylation and activity in relation to measures of inflammation and oxidative stress.
Results
Greater cPLA2 phosphorylation and activity were identified in ApoE4 compared to ApoE3 in primary astrocytes and brains of ApoE-targeted replacement (ApoE-TR) mice. These differences were also demonstrated in brain homogenates from the inferior frontal cortex from AD patients carrying APOE3/4 compared to APOE3/3. Higher cPLA2 activation with APOE4 was associated with greater activation of the MAPK p38 pathway, as well as with higher levels of leukotriene B4 (LTB4), reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS). Inhibition of cPLA2 reduced LTB4, ROS and iNOS levels in ApoE4 primary astrocytes to those of ApoE3 astrocytes.
Conclusions
Our findings implicate greater activation of cPLA2 signaling system with APOE4, that could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
This is a list of supplementary files associated with this preprint. Click to download.
- FigureS1.jpg
ApoE4 increases cPLA2 expression in immortalized ApoE astrocytic cultures. A, cPLA2 mRNA levels in immortalized ApoE3 and ApoE4 astrocytes. B, cPLA2 and phosphorylated cPLA2 (p-cPLA2) protein levels in immortalized ApoE3 and ApoE4 astrocytes (left) were detected by western-blot (WB).
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