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Mechanisms of neuroinflammation with APOE4 implicate CPLA2
Author(s) -
Wang Shaowei,
Solomon Victoria A.,
Sullivan Patrick M.,
Yassine Hussein N.
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.041173
Subject(s) - neuroinflammation , phosphorylation , mapk/erk pathway , protein kinase a , p38 mitogen activated protein kinases , hippocampus , endocrinology , kinase , biology , medicine , arachidonic acid , microbiology and biotechnology , inflammation , biochemistry , enzyme
Background APOE4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD) and is associated with increased susceptibility to neuroinflammation, however the reasons for this association are not very clear. Increased phosphorylation of calcium‐dependent cytosolic PLA2 (cPLA2) is evident in amyloid plaques of human brains. Enhanced cPLA2 activity promotes the release of arachidonic acid (AA) and prostaglandin E₂ (PGE2) to initiate an inflammatory response. Our primary aim is to determine if ApoE4 increases cPLA2 activity. Method Cellular, animal models and human brain tissue were employed Result We found greater cPLA2 expression and phosphorylation in ApoE4 immortalized and primary astrocytes compared to ApoE3. Greater levels of phosphorylated cPLA2 and higher cPLA2 activity were found in the brains of ApoE4‐TR mice (vs ApoE3) at 8‐months of age. In addition, phosphorylated cPLA2 level was increased in hippocampus of APOE4/E4 carriers with AD compared to cognitive healthy APOE3/E3 carriers. To examine the mechanisms for phosphorylation of cPLA2, we examined its regulation by the mitogen‐activated protein kinase (MAPK) pathway. We found that the p38 pathway (but not ERKs pathway) was more activated in cells, mouse and human brain samples with ApoE4 genotype compared to ApoE3. Conclusion Our research implicates an ApoE4‐driven cPLA2 activation as a mechanism for the increased susceptibility to neuroinflammation in AD and a potential target for treatment.