Targeting the liver-brain axis: Licochalcone A as a therapeutic agent against HFD-induced neurodegeneration.

The understanding of neurodegenerative diseases is evolving toward a systemic view, highlighting the connection between liver dysfunction and brain impairment, where metabolism and inflammation play central roles. Licochalcone A (LCA), has demonstrated antidiabetic and anti-inflammatory effects. This study aimed to evaluate its neuroprotective effects under metabolic syndrome conditions. For this purpose, male C57BL/6J mice were fed either with control (CT) or high-fat diet (HFD) from weaning. At eight months, animals received intraperitoneal LCA (15 mg/kg/day) or saline three times per week for four weeks. The resulting groups were CT Saline, HFD Saline, and HFD LCA. Cognitive and metabolic alterations were assessed through behavioral tests and glucose/insulin tolerance assays. Peripheral and/or central markers of metabolism, amyloid burden, inflammation, and synapsis were analyzed using histological staining, immunohistochemistry, Golgi staining, Western blot, ELISA, and RT-PCR. The results demonstrated that LCA administration improved metabolic outcomes by reducing body and liver weight, enhancing glucose tolerance, and improving liver histology. These effects were associated with modulation of insulin signaling pathways, including PTP1B inhibition and AKT activation in the liver and the hippocampus. LCA also reduced HFD-induced Aβ accumulation, which was accompanied by increased LRP1 expression, and attenuated the expression of inflammatory related markers, such as TLR4 and glial activation. Moreover, these improvements were associated with increased levels of synaptic proteins (BDNF, PSD95, DBN1), and synaptic plasticity markers (P-CREB and P-LIMK1), along with preservation of dendritic spine density and improved memory performance. In conclusion, these findings support LCA as a promising candidate for treating HFD-induced neurodegenerative conditions, acting through modulation of metabolic and inflammatory pathways across the liver-brain axis.