Alzheimer's disease (AD) is a complex neurodegenerative disorder with an etiology influenced by various genetic and environmental factors. Heavy metals, such as lead (Pb), have been implicated in AD pathogenesis, but the underlying mechanisms remain poorly understood. This study investigates the potential neurodegenerative role of Pb and amyloid β peptides (1-40 and 25-35) via their interaction with cyclin-dependent kinase 5 (CDK5) and its activator, p25, in an attempt to unravel the molecular basis of Pb-induced neurotoxicity in neuronal cells. To this end, a CDK5 inhibitor was utilized to selectively inhibit CDK5 activity and investigate its impact on neurodegeneration. The results revealed that Pb exposure led to elevated Pb uptake (56.7% at 15 μM Pb) and disturbances in intracellular calcium (19.6% increase upon Pb treatment). The results revealed a significant decrease in total antioxidant capacity (by 88.6% upon Pb treatment) and also elevation in protein carbonylation (by 26.2% upon Pb and Aβp's combination treatment), indicative of oxidative damage, suggesting an impaired cellular defence against oxidative stress and elevated DNA oxidative damage (178 pg/ml and 182 pg/ml of 8-OH-dG upon Pb and All treatment). Additionally, dysregulations in levels of calpain, p25-35 and CDK5 are observed and markers associated with antioxidant metabolism (phospho-Peroxiredoxin 1), DNA damage responses (phospho-ATM and phospho-p53), and nuclear membrane disruption (phospho-lamin A/C) were observed, supporting the role of Pb-induced CDK5-p25 signaling in AD pathogenesis. These findings shed light on the intricate molecular events underlying Pb-induced neurotoxicity and provide valuable insights into the mechanisms that contribute to AD development.
Keywords: Alzheimer’s disease; Calcium dysregulation; Calpain activation; DNA damage; Heavy metals; Lead (Pb); Neurodegeneration; p25-CDK5.
© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.