Licochalcone a enhances cognitive resilience in APP/PS1 Mice by modulating glucose metabolism, Aβ burden, and neuroinflammation

Alzheimer's disease (AD) is a complex neurodegenerative disorder. Current therapeutic approaches targeting a single pathway have shown limited efficacy, highlighting the need for multi-target interventions. Licochalcone A (LCA), a chalcone of licorice root, has demonstrated anti-inflammatory and antidiabetic properties. However, its potential neuroprotective mechanisms in AD remain unclear. The present study aims to elucidate the beneficial effect of LCA against cognitive decline in an AD mouse model. For this purpose, five-month-old APPswe/PS1dE9 (APP/PS1) mice received intraperitoneal LCA (15 mg·kg−1·day−1) treatment for 4 weeks. Afterwards, cognitive function was assessed using Morris water maze (MWM) and Novel object recognition test (NORT). Metabolism was evaluated through glucose and insulin tolerance tests. Biochemical markers of synapses, neurogenesis, metabolism, Amyloid-β (Aβ) burden and neuroinflammation were analyzed using immunohistochemistry, Thioflavin-S staining, Golgi staining, Western blot, ELISA and RT-PCR. The results demonstrated that LCA significantly improved long-term memory in APP/PS1 mice, through MWM and NORT, accompanied by an increased dendritic spine density, upregulated PSD95 and spinophilin levels, and enhanced Ki67-positive cells in the hippocampus. Moreover, LCA treatment ameliorated glucose tolerance and initial insulin response while increasing Insr expression and GLUT1 protein levels. Furthermore, LCA-treated APP/PS1 mice showed reduced plaque burden and Aβ42 levels. Alongside, LCA demonstrated its anti-inflammatory effect by reducing glial reactivity, and Trem2 expression. In conclusion, the present study demonstrates the multiple therapeutic effects of LCA in APP/PS1 mice by simultaneously modulating glucose metabolism, reducing Aβ accumulation and attenuating neuroinflammation, ultimately enhancing cognitive resilience. These findings establish LCA as a promising multi-target compound for AD treatment.