Microglial Dysfunction Mediated by Pb and Amyloid Beta Peptides as a Possible Mechanism of Neurotoxicity.

Abstract

This study delves into the inflammatory and degenerative impacts of lead (Pb) toxicity and amyloid beta peptides (Aβ-peptide 1-40 and Aβ-peptide 25-35) on brain cells, particularly by fostering M1 polarization in microglial cells and subsequent neuronal cell death, crucial in conditions like Alzheimer's disease. Microglia were exposed to IC₅₀ concentrations of Pb, and Aβ-peptide 1-40 and Aβ-peptide 25-35 exhibited notable increases in intracellular ROS levels (32.95%) upon exposure to combinatorial treatments. Moreover, there was a significant decline in total antioxidant capacity to 69.57%, suggesting oxidative damage and compromised cellular defenses against stress, coupled with heightened glutamate levels (921.3 μM). Treatment with Pb alongside Aβ-peptide 1-40 and Aβ-peptide 25-35 also led to elevated intracellular calcium levels (33.83%) and increased production of pro-inflammatory cytokines IL-6 (5.54 pg/mL), TNF-α (5.8 pg/mL), and IFN-γ (13.52 pg/mL) and reduced levels of anti-inflammatory cytokines IL-10 (5.61 pg/mL) and IL-4 (14.46 pg/mL) in microglial cells compared with the control group. Furthermore, upregulation of NF-κB/p65 pathway-associated markers was observed, and when co-cultured with neuronal cells for 24 h, polarized microglia induced neuronal cell death (57.9%). These findings provide insights into the complex molecular mechanisms involved in lead-induced neurotoxicity and neurodegenerative disorders.