Atraric Acid Ameliorates Neurological Dysfunction in High-Fat Diet-Fed Mice by Activating Autophagy to Alleviate...

The ability of atraric acid (AA), a lichen-derived metabolite with anti-inflammatory/antioxidant properties, to protect against obesity-associated neurological dysfunctions was investigated given the role of obesity in triggering neuroinflammation via free fatty acids. Model mice were fed a high-fat diet (HFD) for 12 weeks, and HT22 neurons were exposed to oleic acid/palmitic acid (OA/PA). A variety of experimental techniques, including CCK8, H&E staining, Nissl staining, QPCR, and behavioral tests (open field, elevated plus maze, and Morris water maze), have been used to assess cognitive/anxiety phenotypes. Molecular analyses, including ELISAs (TNF-α/IL-6/GM-CSF), biochemical assays (oxidative stress markers), immunofluorescence/Western blotting, H₂DCFDA-based ROS quantification, and 3-methyladenine (3MA) autophagy blockade, were also performed. The results revealed that AA effectively alleviated anxiety- and depression-like behaviors in HFD-fed mice, as demonstrated by the results of open field and elevated plus-maze tests. AA also significantly mitigated the cognitive decline observed in behavioral assessments, such as the Morris water maze test. Furthermore, AA protected against structural damage and neuronal death in the hippocampal CA1 region. ELISAs and biochemical assays revealed that increasing concentrations of atraric acid significantly reduced the levels of the neuronal injury markers NSE and S100β, as well as the proinflammatory cytokines TNF-α, IL-6, and GM-CSF. Western blot analysis confirmed that AA activated autophagy via the mTOR signaling pathway, thereby reducing oxidative stress, attenuating neuroinflammation, and ultimately improving cognitive impairment in mice. In conclusion, this study demonstrated that the protective effect of AA against HFD-induced cognitive impairment is associated with the activation of autophagy, a reduction in oxidative stress, and the alleviation of neuroinflammation. Our findings demonstrate the neuroprotective properties of atraric acid in preclinical models, providing a rationale for further investigation as a potential candidate for treating cognitive dysfunction.