Amyloid beta levels and occludin depletion in low dose heavy metal mixture mediated cerebellar toxicity in Wistar rats

Abstract

Co-exposure to heavy metals can result in additive or synergistic toxicity in the brain, culminating in neurotoxicity. This study investigated the neurotoxic effects of a low-dose mixture of two toxic heavy metals-lead (Pb, 20 mg/kg) and aluminium (Al, 35 mg/kg)-and one essential metal, manganese (Mn, 0.564 mg/kg), on the cerebellum of rats. Animals were divided into five groups (n = 5) and orally treated for 90 days as follows: Group I received normal drinking water and served as the control; Group II received a heavy metal mixture of Pb (20 mg/kg), Al (35 mg/kg), and Mn (0.564 mg/kg) body weight; Group III received Pb (20 mg/kg) alone; Group IV received Al (35 mg/kg) alone; and Group V received Mn (0.564 mg/kg) alone. Chronic exposure to heavy metals resulted in a significant (p < 0.05) reduction in rotarod performance compared with the control group, indicating impaired cerebellar motor function. The low-dose heavy metal mixture significantly depressed antioxidant defences (p < 0.05), increased lipid peroxidation (p < 0.05), elevated amyloid-β peptide levels (Aβ₁-₄₀ and Aβ₁-₄₂) (p < 0.05), and markedly reduced occludin expression (p < 0.05) in the cerebellum relative to controls. These biochemical alterations were more pronounced in the mixture-exposed group than in animals treated with individual metals. Overall, chronic low-dose exposure to an environmentally relevant heavy metal mixture induces cerebellar neurotoxicity through enhanced amyloid-β accumulation and downregulation of occludin, a key tight junction protein, in adult male Wistar rats. These findings underscore the role of mixed metal exposure in amyloid-β dysregulation, tight junction disruption, and cerebellar dysfunction.