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Titanium dioxide and carbon black nanoparticles disrupt neuronal homeostasis via excessive activation of cellular prion protein signaling

Abstract : Background: Epidemiological emerging evidence shows that human exposure to some nanosized materials present in the environment would contribute to the onset and/or progression of Alzheimer's disease (AD). The cellular and molecular mechanisms whereby nanoparticles would exert some adverse effects towards neurons and take part in AD pathology are nevertheless unknown. Results: Here, we provide the prime evidence that titanium dioxide (TiO 2) and carbon black (CB) nanoparticles (NPs) bind the cellular form of the prion protein (PrP C), a plasma membrane protein well known for its implication in prion diseases and prion-like diseases, such as AD. The interaction between TiO 2-or CB-NPs and PrP C at the surface of neuronal cells grown in culture corrupts PrP C signaling function. This triggers PrP C-dependent activation of NADPH oxidase and subsequent production of reactive oxygen species (ROS) that alters redox equilibrium. Through PrP C interaction, NPs also promote the activation of 3-phosphoinositide-dependent kinase 1 (PDK1), which in turn provokes the internalization of the neuroprotective TACE α-secretase. This diverts TACE cleavage activity away from (i) TNFα receptors (TNFR), whose accumulation at the plasma membrane augments the vulnerability of NP-exposed neuronal cells to TNFα-associated inflammation, and (ii) the amyloid precursor protein APP, leading to overproduction of neurotoxic amyloid Aβ40/42 peptides. The silencing of PrP C or the pharmacological inhibition of PDK1 protects neuronal cells from TiO 2-and CB-NPs effects regarding ROS production, TNFα hypersensitivity, and Aβ rise. Finally, we show that dysregulation of the PrP C-PDK1-TACE pathway likely occurs in the brain of mice injected with TiO 2-NPs by the intra-cerebro-ventricular route as we monitor a rise of TNFR at the cell surface of several groups of neurons located in distinct brain areas. Conclusion: Our in vitro and in vivo study thus posits for the first time normal cellular prion protein PrP C as being a neuronal receptor of TiO 2-and CB-NPs and identifies PrP C-coupled signaling pathways by which those nanoparticles alter redox equilibrium, augment the intrinsic sensitivity of neurons to neuroinflammation, and provoke a rise of Aβ
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Submitted on : Tuesday, July 26, 2022 - 11:59:41 AM
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Luiz W. Ribeiro, Mathé Pietri, Hector Ardila-Osorio, Anne Baudry, François Boudet-Devaud, et al.. Titanium dioxide and carbon black nanoparticles disrupt neuronal homeostasis via excessive activation of cellular prion protein signaling. Particle and Fibre Toxicology, BioMed Central, 2022, 19 (1), pp.48. ⟨10.1186/s12989-022-00490-x⟩. ⟨anses-03736622⟩



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