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 (TiO2) and carbon black (CB) nanoparticles (NPs) bind the cellular form of the prion protein (PrPC), a plasma membrane protein well known for its implication in prion diseases and prion-like diseases, such as AD. The interaction between TiO2- or CB-NPs and PrPC at the surface of neuronal cells grown in culture corrupts PrPC signaling function. This triggers PrPC-dependent activation of NADPH oxidase and subsequent production of reactive oxygen species (ROS) that alters redox equilibrium. Through PrPC 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 PrPC or the pharmacological inhibition of PDK1 protects neuronal cells from TiO2- and CB-NPs effects regarding ROS production, TNFα hypersensitivity, and Aβ rise. Finally, we show that dysregulation of the PrPC-PDK1-TACE pathway likely occurs in the brain of mice injected with TiO2-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 PrPC as being a neuronal receptor of TiO2- and CB-NPs and identifies PrPC-coupled signaling pathways by which those nanoparticles alter redox equilibrium, augment the intrinsic sensitivity of neurons to neuroinflammation, and provoke a rise of Aβ peptides. By identifying signaling cascades dysregulated by TiO2- and CB-NPs in neurons, our data shed light on how human exposure to some NPs might be related to AD.

Modulation efficiency of clove oil nano-emulsion against genotoxic, oxidative stress, and histological injuries induced via titanium dioxide nanoparticles in mice

“…The increased production of ROS after administration of TiO 2 -NPs may be rationalized by activation of heme oxygenase 1 through p38-Nrf-2 signaling pathway or attachment of TiO 2 -NPs to prion protein the plasma membrane protein which distorts prion signaling function. This prompts the activation of NADPH oxidase via prion-dependent pathway and consequently increases the production of ROS that changes redox equilibrium 44 , 45 .…”

Neurotoxicity of Titanium Dioxide Nanoparticles: A Comprehensive Review

“…178 Furthermore, exposure to TiO 2 NPs was associated with varying degrees of cytotoxicity to the human cerebral endothelial cell line (HCECs), human neural stem cell line (hNSCs), and neuroectodermal stem cell line (1C11) models. [179][180][181] See Table 7 for details. The neurotoxic effects of TiO 2 NPs are influenced by various factors.…”

From Mechanisms to Implications: Understanding the Molecular Neurotoxicity of Titanium Dioxide Nanoparticles

“…In addition to aggregation of α-synuclein and tau protein, TiO 2 NPs were also shown to have a significant effect on β-amyloid production. Ribeiro et al (2022) [124] demonstrated that direct interaction of TiO 2 NPs with neuronal membrane prion protein (PrP C ) results in activation of NADPH-oxidase and 3-phosphoinositide-dependent kinase 1 (PDK1) with subsequent internalization of TACE αsecretase, resulting in increased sensitivity to TNFα and accumulation of amyloid precursor protein with amyloid Aβ40/42 overproduction. In addition, genotoxic effects of oral TiO 2 NP exposure evidenced by DNA fragmentation were also associated with a point mutation at exon 5 of PSEN1 gene that is known to be associated with inherited forms of Alzheimer's disease [125].…”