SG06, a Chalcone Derivative Targets PI3K/AKT1 Pathway for Neuroprotection and Cognitive Enhancement in an Alzheimer's Disease-Like Zebrafish Model.

Alzheimer's disease (AD) and Alzheimer's dementia (ADM) are common neurodegenerative disorders marked by progressive cognitive decline, memory impairment, and behavioral deficits, which impose a significant burden on individuals and healthcare systems worldwide. Due to the complex nature of AD pathophysiology, effective treatment strategies may require targeting multiple pathways. This study explored the neuroprotective effects of the chalcone derivative SG06 in a scopolamine-induced AD-like zebrafish model using network pharmacology and molecular docking. SG06 showed strong binding to key targets such as AKT serine/threonine kinase 1 (AKT1), which are involved in processes like tau phosphorylation, amyloid-beta (Aβ) production, and inflammation. Behavioral assays indicated that SG06 improved cognitive function, reduced anxiety-like behavior, and restored social interactions. Additionally, sensory recovery was observed through better light/dark transitions and recovered olfactory function, likely due to improved neuronal communication and reduced oxidative stress. Mechanistically, SG06 appeared to activate the PI3K/AKT1 pathway, inhibiting Glycogen Synthase Kinase 3 beta (GSK3β) activity, which may help reduce tau hyperphosphorylation and amyloid processing. SG06 also restored antioxidant markers (CAT, GSH, GPx) and improved acetylcholinesterase (AChE) activity, reducing oxidative damage and cholinergic dysfunction. Histological analysis revealed improved cellular morphology and decreased Aβ plaque accumulation, while gene expression studies showed downregulation of pro-inflammatory markers and upregulation of neuroprotective genes. Additionally, SG06 helped improving neurotransmitter balance, particularly in Gamma-Aminobutyric Acid (GABA) and Dopamine (DPAN), contributing to improved synaptic plasticity and cognitive function. These findings suggest that SG06 may have potential as a multi-target therapeutic agent in addressing the complex pathology of AD.