Human apolipoprotein E ε4 allele modulates energy substrate availability, seizure burden, mortality and hippocampal injury, cell death and inflammation after neonatal hypoxic-ischemic brain injury.
Academic Article
Overview
abstract
INTRODUCTION: Human apolipoprotein E allele ε4 (ApoE4) is the strongest genetic risk factor for some forms of adulthood neurodegeneration linked to energetic disturbances and inflammation. We hypothesized that ApoE4 also influences neonatal brain neurodegeneration after a hypoxic ischemic (HI) insult, resulting in energy substrates (i.e., glucose, ketone bodies) disturbances, hippocampal injury, cell death and inflammation. METHODS: Right-sided brain HI was induced at P10 in wild type (wt, C57BL6) and humanized ApoE3 and ApoE4 mice with sham anesthesia-exposed littermates as controls. Seizure-like activity, survival, blood glucose (BG), and ketone bodies (KB) were determined immediately after the HI insult. The hippocampi were assessed 24h and 72h after the HI insult for residual volume, cell death (α-fodrin breakdown), inflammatory markers, and transcriptomics (RNAseq). RESULTS: Wt, ApoE3 and ApoE4 mice were congenic (>99.8% transcriptome similarity). Female ApoE4 mice had worse seizures, lower survival and smaller residual hippocampal volumes than the ApoE3 mice. All three strains had lower BG after HI. ApoE4 mice also had lower KB. Low BG was associated with higher pro-inflammatory and cell death markers in the hippocampus in all HI genotype groups at 24h but more robustly in ApoE4 mice, and in combination with high KB, was strongly linked to cell death (greater α-fodrin breakdown). CONCLUSION: Humanized ApoE4, compared to ApoE3, causes greater hippocampal injury, cell death and inflammation after a neonatal HI insult in association with low BG and underutilized KB. The mechanisms behind these associations need further investigation.
