Alzheimer’s disease is a neurodegenerative condition causing cognitive decline. Aluminum chloride (AlCl3) is a neurotoxin linked to oxidative stress and neurodegenerative disorders. In light of inadequate current treatments, there is an urgent need for more approaches to treat Alzheimer’s disease. β-sitosterol, a phytosterol found in grape skin, fern, and red wine, has potential health benefits. This research aims to assess its preventive impact on AlCl3-induced Alzheimer’s disease. The animals were divided into five groups: Group I (control), Group II (AlCl3 70 mg/kg), Group III (Rivastigmine 2.3 mg/kg), and Groups IV and V (β-sitosterol 50 and 100 mg/kg with AlCl3). AlCl3 was administered from days 5–25, treatments from 26–42 days, and behavioral parameters were measured on days 5, 16, 26, and 42, after which brain samples were collected for the estimation level of oxidative stress, cholinergic function, Glycogen synthase kinase-3β, Rho kinase, Lipoxygenase-5, TNF-α, COX-2, and Na+K+ATPase expression and activity. The β-sitosterol prevented cognitive impairment caused by AlCl3 via the reduction of oxidative stress, the improvement of cholinergic function, and the suppression of Glycogen synthase kinase-3β, Rho kinase, Lipoxygenase-5, TNF-α, COX-2, and Na+K+ATPase expression and activity. In silico studies demonstrated the strong affinity of β-sitosterol towards Alzheimer’s disease biomarkers, confirming their function in preventing and regulating its pathogenesis. Consequently, the findings point out that β-sitosterol has an anti-Alzheimer’s ability by reducing the toxicity caused by AlCl3.
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