Hippocampal Hbα deficiency induces neuronal apoptosis by promoting the accumulation of AGEs

Hemoglobin alpha (Hbα) is localized to neuronal mitochondria, but its role in neuronal health remains unclear. We investigated the impact of Hbα deficiency in hippocampal neurons, focusing on advanced glycation end products (AGEs). Using adeno-associated virus‌-mediated silencing, we found hippocampal Hbα-deficient mice showed spatial memory deficits and pyramidal neuron loss. Molecular analysis revealed that Hbα depletion downregulated mitochondrial biogenesis (peroxisome proliferator-activated receptor gamma coactivator 1α) and disrupted mitochondrial membrane proteins. This was accompanied by increased accumulation of AGEs, elevated levels of the inflammatory factor interleukin-1β and enhancing pro-apoptotic signaling. Consistently, Hbα depletion in HT22 hippocampal neuronal cells compromised cell viability, and this deficit was rescued by treatment with the AGEs inhibitor alagebrium (ALT711). Furthermore, ALT711 treatment modulated mitochondrial membrane integrity and attenuated pro-apoptotic signaling. Our findings indicate Hbα maintains neuronal health by modulating AGEs and inhibiting apoptosis, suggesting AGEs inhibition as a therapeutic strategy for Hbα deficiency-related damage.