Atraric acid enhances neuronal survival and cognition against D-galactose-induced neurodegeneration via BDNF/TrkB/AKT signaling.

Aging-induced neurodegeneration is characterized by cognitive impairment, elevated oxidative stress, neuroinflammation, synaptic loss, and neuronal death. Atraric acid (AA), a phenolic compound obtained from lichens, is reported to have potent anti-inflammatory and antioxidant effects in various disease models. However, aging-induced cognitive impairment and dementia are still not elucidated. To fill this gap, we investigated AA (20 mg/kg/day, intraperitoneally (i.p.) for 4 weeks) against D-galactose (D-gal) (120 mg/kg/day, i.p. for 8 weeks)-induced brain senescence and memory dysfunction in mice. Behavioral tests, including NOR, MWM, and Y-maze, were conducted to assess cognitive function, followed by biochemical and immunofluorescence analyses. AA restored the BDNF/TrkB/Akt signaling axis disrupted by D-gal administration. Furthermore, immunoblotting for Nrf-2 and HO-1 revealed elevated expression in the mouse cortex and hippocampus. AA also enhanced antioxidant enzymes, including glutathione (GSH), glutathione S-transferase (GST), catalase (CAT), and superoxide dismutase (SOD), while reducing lipid peroxidation (LPO), thereby supporting its antioxidant role. Moreover, D-gal enhanced NF-kB-mediated neuroinflammation, apoptotic markers including caspase-3 and PARP-1, and suppressed synaptic proteins (SNAP-23 and PSD-95). Interestingly, these expression aberrations were reversed upon AA administration. Histological analyses using Nissl and Fluoro-Jade B staining further supported neuronal protection in the cortex and hippocampus. Collectively, these findings suggest that AA exerts neuroprotective effects against D-gal-induced aging and cognitive decline by reducing oxidative stress, neuroinflammation, neuronal apoptosis, and enhancing synaptic plasticity through BDNF/TrkB/Akt/CREB signaling.