Neuroprotective Effects of Molecular Hydrogen via Oxidative Stress and Neuroinflammation Regulation in a 5xFAD Mouse Model.

Abstract

Using the 5xFAD transgenic mouse model carrying human APP and PSEN1 mutations, this study examined the effects of daily 2% H2 gas inhalation (1 h/day, 4 weeks) on amyloid-driven neuropathology. H2 exposure reduced hippocampal reactive oxygen species and elevated systemic catalase activity, while hippocampal ATP levels were improved, suggesting enhanced mitochondrial function. In serum, pro-inflammatory cytokines TNF-α and IL-1β declined, whereas IL-10 was restored and IL-13 was partially normalized, indicating a shift toward an anti-inflammatory peripheral milieu. Within the hippocampus, NRF2 was upregulated, NF-κB activation was attenuated, the BAX/BCL-2 apoptotic ratio decreased, NeuN-positive neuronal populations were preserved, and Aβ42 burden was reduced. These results collectively demonstrate that H2 inhalation provides multi-target neuroprotection in this AD model by simultaneously addressing redox imbalance, inflammatory signaling, apoptotic pathways, and amyloid accumulation.

Mechanism

H2 inhalation activates NRF2 to reduce oxidative stress, suppresses NF-κB-driven neuroinflammation, lowers the BAX/BCL-2 apoptotic ratio, improves mitochondrial ATP production, and decreases hippocampal Aβ42 accumulation, collectively preserving neuronal integrity in amyloid-laden tissue.