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Unveiling Potential Neurotoxic Mechansisms: Pb-Induced Activation of CDK5-p25 Signaling Axis in Alzheimer’s Disease Development, Emphasizing CDK5 Inhibition and Formation of Toxic p25 Species

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Abstract

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.

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Acknowledgements

We thank the Indian Council of Medical Research (ICMR) for providing funds to carryout research and the University grants commission (UGC), Government of India for the award of fellowship.

Funding

This work was supported by the Grant 58/57/2012-BMS funded by Indian council of medical research (ICMR).

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  1. Cell Biology Division, National Institute of Nutrition, Indian Council of Medical Research (ICMR), Hyderabad, Telangana, 500007, India

    Murumulla Lokesh, Lakshmi Jaya Madhuri Bandaru, Ajumeera Rajanna, J. Sreenivasa Rao & Suresh Challa

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  1. Murumulla Lokesh
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ML performed all the experiments, did data analysis, and drafted the manuscript. SC proposed the idea and critically revised the work. LJMB assisted in conducting experiments. AR assisted in conducting FACS experiments, and J.S assisted in editing the manuscript.

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Correspondence to Suresh Challa.

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Lokesh, M., Bandaru, L.J.M., Rajanna, A. et al. Unveiling Potential Neurotoxic Mechansisms: Pb-Induced Activation of CDK5-p25 Signaling Axis in Alzheimer’s Disease Development, Emphasizing CDK5 Inhibition and Formation of Toxic p25 Species. Mol Neurobiol 61, 3090–3103 (2024). https://doi.org/10.1007/s12035-023-03783-0

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