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

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 (PrP^C), 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 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 TiO₂- 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 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 PrP^C as being a neuronal receptor of TiO₂- 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 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.