Pediatrics and neonatology · 2026
Mechanisms of Aβ1-42-mediated oxidative stress-induced neuronal apoptosis in neonatal hypoxic-ischemic brain injury.
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Hou Lixuan, Li Lihua
Аннотация
OBJECTIVE: Neonatal hypoxic-ischemic brain damage (HIBD) is a leading cause of acute mortality and long-term neurological impairment in newborns. Previous studies indicate that hypoxia-ischemia induces aberrant elevation of amyloid-beta (Aβ)1-42, which exacerbates neuronal injury through oxidative stress. However, the mechanistic link between Aβ1-42 and oxidative stress-mediated apoptosis in HIBD remains unclear. This study aimed to elucidate the role of Aβ1-42 in oxidative stress-induced neuronal damage during HIBD and explore the therapeutic potential of targeting β-secretase 1(BACE1).
METHODS: In vivo, a neonatal HIBD model was established in 10-day-old Sprague-Dawley rats via right common carotid artery ligation followed by 2.5 h of hypoxia (8% O2/92% N2). In vitro, primary cortical neurons isolated from embryonic day 16-18 rats were subjected to oxygen-glucose deprivation/reperfusion (OGD/R). The BACE1 inhibitor AZD3293 (30 mg/kg, oral gavage) was administered immediately post-injury. Aβ1-42 levels were quantified by ELISA, while BACE1, BCL-2, and cleaved caspase-3 expression were analyzed via Western blot. Cellular viability was assessed using the MTT assay, and oxidative stress markers (SOD activity, MDA, and ROS levels) were measured using colorimetric/fluorometric kits.
RESULTS: In vivo: Aβ1-42 levels peaked at 8 h post-HIBD. Administration of the BACE1 inhibitor significantly reduced Aβ1-42, BACE1, and cleaved caspase-3 levels compared to the HIBD 8 h group. Conversely, BCL-2 expression was upregulated.
IN VITRO: Aβ1-42 accumulation peaked at 8 h post-OGD/R, paralleled by increased BACE1 expression at 24 h, elevated cleaved caspase-3 at 8 h, and reduced BCL-2 at 8 h. OGD/R induced time-dependent declines in cell viability, SOD activity, and increases in MDA and ROS. BACE1 inhibition mitigated these oxidative stress markers and apoptosis.
CONCLUSION: Hypoxic-ischemic injury upregulates BACE1, inducing Aβ1-42 overproduction. This exacerbates oxidative stress in HIBD, establishing a feed-forward loop that culminates in neuronal apoptosis.
METHODS: In vivo, a neonatal HIBD model was established in 10-day-old Sprague-Dawley rats via right common carotid artery ligation followed by 2.5 h of hypoxia (8% O2/92% N2). In vitro, primary cortical neurons isolated from embryonic day 16-18 rats were subjected to oxygen-glucose deprivation/reperfusion (OGD/R). The BACE1 inhibitor AZD3293 (30 mg/kg, oral gavage) was administered immediately post-injury. Aβ1-42 levels were quantified by ELISA, while BACE1, BCL-2, and cleaved caspase-3 expression were analyzed via Western blot. Cellular viability was assessed using the MTT assay, and oxidative stress markers (SOD activity, MDA, and ROS levels) were measured using colorimetric/fluorometric kits.
RESULTS: In vivo: Aβ1-42 levels peaked at 8 h post-HIBD. Administration of the BACE1 inhibitor significantly reduced Aβ1-42, BACE1, and cleaved caspase-3 levels compared to the HIBD 8 h group. Conversely, BCL-2 expression was upregulated.
IN VITRO: Aβ1-42 accumulation peaked at 8 h post-OGD/R, paralleled by increased BACE1 expression at 24 h, elevated cleaved caspase-3 at 8 h, and reduced BCL-2 at 8 h. OGD/R induced time-dependent declines in cell viability, SOD activity, and increases in MDA and ROS. BACE1 inhibition mitigated these oxidative stress markers and apoptosis.
CONCLUSION: Hypoxic-ischemic injury upregulates BACE1, inducing Aβ1-42 overproduction. This exacerbates oxidative stress in HIBD, establishing a feed-forward loop that culminates in neuronal apoptosis.