APOE4 and Brain Inflammation

Although the mechanisms are not clear, APOE4 is associated with an increased response to neuroinflammation and a higher risk of developing late-onset Alzheimer’s disease (AD). Here in the Yassine Lab, we wanted to further understand the relationship between APOE4 genotype and cPLA2 activity. cPLA2 activation is involved in inflammatory signaling and becomes elevated within the plaques of AD brains. This was identified in clinical studies that noted greater cPLA2 activation around AD brain plaques and in the CSF of patients with AD. We executed this research through experiments that used Mouse primary astrocytes along with mouse and human brain samples. These specimens had differing APOE genotypes and were collected to evaluate cPLA2 expression, phosphorylation, and measures of inflammation and oxidative stress. The observations that came from this research were astonishing. In the primary astrocytes, brains of ApoE-targeted replacement mice, and in human brain homogenates of patients with AD dementia, higher cPLA2 activity, and greater cPLA2 phosphorylation were identified in ApoE4 compared to ApoE3. Along with this, increased cPLA2 translocation to cytosol was observed in human postmortem frontal cortical synaptosomes with recombinant ApoE4 than ApoE3 ex vivo. 

Throughout this research, our findings implicate greater activation of the cPLA2 signaling system with APOE4. This can be monumental in playing a role as a potential drug target for mitigating the increased neuroinflammation with APOE4 and AD.

To learn more about this publication please visit https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-022-00549-5

ApoE4 increases cPLA2 but not iPLA2 expression in mouse primary astrocytes. Primary astrocytes were cultured from the cortex of P1-P4 mouse pups. A cPLA2 mRNA levels in primary astrocytes from ApoE3 and ApoE4-TR mice were measured by qPCR. B cPLA2, and phosphorylated cPLA2 (p-cPLA2) protein levels in primary astrocytes from ApoE3 and ApoE4-TR mice were detected by Western blot. C iPLA2 mRNA levels in primary astrocytes from ApoE3 and ApoE4-TR mice. D iPLA2 protein levels in primary astrocyte cultures from ApoE3 and ApoE4-TR mice were detected by Western blot. (n = 3 for each genotype for A-D). E, F Primary astrocytes from ApoE3 and ApoE4-TR mice were incubated with 3H-labelled AA (E) or 14C-labeled DHA (F) for 24 h, followed by induction by 100 nM ATP for 15 min. The efflux of 3H-AA (E) and 14C-DHA (F) from cells to media was measured by scintillation counting. G, H Primary astrocytes from C57BL/6 wild-type mice were labeled with H-AA (G) or 14C-DHA (H) for 24 hr, and then treated with rE3 or rE4 (0.2 μM) for 24 hours, followed by induction with 100 nM ATP for 15 min. 3H-AA (G) and 14C-DHA (H) efflux were measured by scintillation counting (n = 3 for E-H). Data are represented as mean ± SEM and analyzed by Student’s t-test (two-tailed). *p < 0.05, **p < 0.01. rE3: recombinant ApoE3, rE4: recombinant ApoE4

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