In Alzheimer's disease (AD), the hippocampus and cerebral cortex are primarily affected, showing degeneration of cholinergic neurons and Aβ plaques accumulation. These changes are strongly associated with oxidative stress, neuroinflammation, and impaired autophagy. In our study simvastatin (Simva), a lipid-lowering statin, was investigated against aluminum chloride (AlCl)-induced rat model of AD and showed potential neuroprotective effects. Nano-delivery systems were used to enhance Simva's brain pharmacological activity. Adult male Sprague Dawley rats were designated into four groups: Control group (normal saline, IP, 28 days), AlClgroup (25 mg/kg AlCl, IP for 28 days), Simva group (Simva 10 mg/kg, orally for 28 days 1 h before AlClinjection) and Simva-Nano group (Simva nanocarrier 10 mg/kg, orally for 28 days 1 h before AlClinjection). Simva and its nanocarrier enhanced autophagy by upregulating p-AMPK, p-ULK1, and LC3-II while downregulating ULK1. They showed strong antioxidant and anti-inflammatory effects by decreasing MDA, TNF-α, IL-1β and increased GSH. Additionally, they increased ACh levels and suppressed AChE gene expression. Immunohistochemical staining revealed substantial reduction in Aβ plaques in the Simva group, while in Simva-Nano group, Aβ plaques were not detected under our assay conditions. Aβ immunostaining was quantified as the number of Aβ deposits per field (6 fields). Histopathological analysis confirmed reduced neuronal degeneration and glial activation, with the Simva-Nano group demonstrating near-normal hippocampal architecture. In conclusion, Simva exhibits notable neuroprotective effects in the AD rat model via antioxidative, anti-inflammatory, and autophagic pathways. Nanocarrier delivery further improves Simva's pharmacological effects, offering a promising AD therapeutic strategy. 3 3 3 3 3
