LICOCHALCONE A IMPROVES COGNITIVE FUNCTION THROUGH MODULATION OF SYNAPTIC PLASTICITY-RELATED MIRNAS AND NEUROTRANSMITTERS IN ALZHEIMER’S DISEASE

Altered microRNA expression has recently been described in Alzheimer’s disease (AD) patients and linked to early disease hallmarks, including synaptic dysfunction, neuroinflammation, and monoaminergic imbalance. However, no approved therapies concurrently target these mechanisms or effectively modify disease progression. In this context, Licochalcone A (LCA), a chalcone-type flavonoid with pleiotropic pharmacological properties, remains poorly explored in the context of AD. Here, we assess the disease-modifying potential of LCA in a murine AD model alongside complementary cellular analyses.
Five-month-old APPswe/PS1dE9 male mice received intraperitoneal LCA (15 mg/kg/day, 4 weeks). Subsequently, behavioral tests evaluated cognition and anxiety-like behavior, while molecular analyses assessed monoaminergic transmission, synaptic plasticity, and neuroinflammation. In parallel, the neuroprotective and anti-inflammatory effects of LCA (10 µM) were tested in amyloid-β (Aβ)-exposed primary hippocampal neurons (0.5 µM) and lipopolysaccharide (LPS)-stimulated BV2 cells (50 ng/mL), respectively.
LCA demonstrated its anti-inflammatory effect by reducing pro-inflammatory responses in LPS-stimulated BV2 cells, which was associated with enhanced synaptic plasticity markers, including increased dendritic spine density, in Aβ-exposed hippocampal neurons. Consistently, LCA treatment in vivo modulated synapse-related microRNAs and elevated prefrontal dopamine and serotonin levels, indicating regulation of synaptic plasticity and monoaminergic signaling, two key contributors of cognitive resilience in AD. In line with these molecular effects, LCA improved spatial and recognition memory in object location and novel object recognition tasks, and reduced anxiety-like behavior in the open field.
Collectively, these findings identify LCA as a promising multi-target modulator of AD-related pathways and encourage further investigation of its therapeutic potential in AD.