Developmental neuroscience · 2025
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.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Nazareth Michelle, Duck Sarah Ann, Fassinger Abigail, Elmore Genesis, Pinto Charles, Nugent Michael, St Pierre Mark, Lechner Charles, Jantzie Lauren L, Northington Frances J, Vannucci Susan J, Martin Lee J, Chavez-Valdez Raul
Аннотация
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 [KBs]) 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 KB were determined immediately after the HI insult. The hippocampi were assessed 24 h and 72 h 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 proinflammatory and cell death markers in the hippocampus in all HI genotype groups at 24 h 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.
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 KB were determined immediately after the HI insult. The hippocampi were assessed 24 h and 72 h 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 proinflammatory and cell death markers in the hippocampus in all HI genotype groups at 24 h 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.