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Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4.

Publication ,  Journal Article
Wang, S; Li, B; Solomon, V; Fonteh, A; Rapoport, SI; Bennett, DA; Arvanitakis, Z; Chui, HC; Miller, C; Sullivan, PM; Wang, H-Y; Yassine, HN
Published in: Mol Neurodegener
April 16, 2021

BACKGROUND: Apolipoprotein E4 (APOE4) is associated with a greater response to neuroinflammation and the risk of developing late-onset Alzheimer's disease (AD), but the mechanisms for this association are not clear. The activation of calcium-dependent cytosolic phospholipase A2 (cPLA2) is involved in inflammatory signaling and is elevated within the plaques of AD brains. 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, cPLA2 activity and leukotriene B4 (LTB4) levels were identified in ApoE4 compared to ApoE3 in primary astrocytes, brains of ApoE-targeted replacement (ApoE-TR) mice, and in human brain homogenates from the inferior frontal cortex of patients with AD carrying APOE3/E4 compared to APOE3/E3. Greater cPLA2 phosphorylation was also observed in human postmortem frontal cortical synaptosomes and primary astrocytes after treatment with recombinant ApoE4 ex vivo. In ApoE4 astrocytes, the greater levels of LTB4, reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS) were reduced after cPLA2 inhibition. CONCLUSIONS: Our findings implicate greater activation of cPLA2 signaling system with APOE4, which could represent a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

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Published In

Mol Neurodegener

DOI

EISSN

1750-1326

Publication Date

April 16, 2021

Volume

16

Issue

1

Start / End Page

26

Location

England

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Synaptosomes
  • Reactive Oxygen Species
  • Protein Processing, Post-Translational
  • Phosphorylation
  • Phospholipases A2, Cytosolic
  • Peptide Fragments
  • Oxidative Stress
  • Neurons
  • Neurology & Neurosurgery
 

Citation

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Wang, S., Li, B., Solomon, V., Fonteh, A., Rapoport, S. I., Bennett, D. A., … Yassine, H. N. (2021). Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4. Mol Neurodegener, 16(1), 26. https://doi.org/10.1186/s13024-021-00438-3
Wang, Shaowei, Boyang Li, Victoria Solomon, Alfred Fonteh, Stanley I. Rapoport, David A. Bennett, Zoe Arvanitakis, et al. “Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4.Mol Neurodegener 16, no. 1 (April 16, 2021): 26. https://doi.org/10.1186/s13024-021-00438-3.
Wang S, Li B, Solomon V, Fonteh A, Rapoport SI, Bennett DA, et al. Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4. Mol Neurodegener. 2021 Apr 16;16(1):26.
Wang, Shaowei, et al. “Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4.Mol Neurodegener, vol. 16, no. 1, Apr. 2021, p. 26. Pubmed, doi:10.1186/s13024-021-00438-3.
Wang S, Li B, Solomon V, Fonteh A, Rapoport SI, Bennett DA, Arvanitakis Z, Chui HC, Miller C, Sullivan PM, Wang H-Y, Yassine HN. Calcium-dependent cytosolic phospholipase A2 activation is implicated in neuroinflammation and oxidative stress associated with ApoE4. Mol Neurodegener. 2021 Apr 16;16(1):26.
Journal cover image

Published In

Mol Neurodegener

DOI

EISSN

1750-1326

Publication Date

April 16, 2021

Volume

16

Issue

1

Start / End Page

26

Location

England

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Synaptosomes
  • Reactive Oxygen Species
  • Protein Processing, Post-Translational
  • Phosphorylation
  • Phospholipases A2, Cytosolic
  • Peptide Fragments
  • Oxidative Stress
  • Neurons
  • Neurology & Neurosurgery