α-Lipoic acid mitigates age-related cognitive decline by modulating PPARγ/NF-κB-mediated neuroinflammation

Objective: Age-related cognitive decline is associated with chronic neuroinflammation, and α-lipoic acid (LA) has been proposed as a potential cognitive enhancer. This study aimed to investigate whether LA ameliorates aging-related cognitive impairment by regulating neuroinflammation through the Peroxisome Proliferator-activated Receptor gamma (PPARγ)/nuclear factor kappa B (NF-κB) pathway in vivo and vitro.

Methods: Eighteen-month-old naturally aged C57BL/6 mice were treated with LA (100 mg/kg/day) for 8 weeks, followed by T maze behavioral tests. Immunofluorescence, PCR, and Western blot were used to assess neuroinflammation and PPARγ/NF-κB signaling pathway in the hippocampus. In vitro, D-galactose-induced BV2 cell was used as a senescent model. Cell viability was measured through CCK-8 assay. Subsequent PCR and Western blot analyses further delineated changes in inflammatory cytokines and PPARγ/NF-κB pathway.

Results: LA administration demonstrated significant cognitive-enhancing effects, accompanied by suppression of both microgliosis and astrocytosis, as well as a reduction in pro-inflammatory cytokines in the hippocampus of aged mice. Mechanistically, LA upregulated PPARγ expression and inhibited NF-κB phosphorylation. Furtherly, in vitro, LA attenuated senescence-associated inflammation, an effect that was abolished by the PPARγ Antagonist GW9662, confirming the critical role of PPARγ signaling in mediating LA's anti-inflammatory action.

Conclusions: LA mitigated age-related cognitive deficits by modulating neuroinflammation through PPARγ/NF-κB suppression. Our findings highlighted the therapeutic potential of LA in aging-related cognitive decline and the role of the PPARγ/NF-κB axis in neuroinflammation regulation. As an exploratory study with a limited sample size, these findings offer promising insights that would benefit from future confirmation in larger cohorts.