<figure><img src="image_1.png" /></figure>

HAL
open science

# Original Adverse Outcome Pathway linking neuronal exposure to nanoparticles to the onset of Alzheimer's disease

Benoit Schneider

► To cite this version:

Benoit Schneider. Original Adverse Outcome Pathway linking neuronal exposure to nanoparticles to the onset of Alzheimer's disease. Alzheimer's & Dementia: the Journal of the Alzheimer's Association, 2025, 20 (S1), pp.e087445. 10.1002/alz.087445. hal-05392087

HAL Id: hal-05392087

https://hal.science/hal-05392087v1

Submitted on 2 Dec 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_2.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
<figure><img src="image_3.png" /></figure>

DOI: 10.1002/alz.087445

BASIC SCIENCE AND PATHOGENESIS

POSTER PRESENTATION

MOLECULAR AND CELL BIOLOGY

Alzheimer's & Dementia®
THE JOURNAL OF THE ALZHEIMER'S ASSOCIATION

# Original Adverse Outcome Pathway linking neuronal exposure to nanoparticles to the onset of Alzheimer's disease

Benoit Schneider

Ecole polytechnique - CNRS UMR7654,
Palaiseau, Ile-de-France, France; Université
Paris Cité - Inserm UMR-S1124, Paris,
Ile-de-France, France

**Correspondence**

Benoit Schneider, Ecole polytechnique - CNRS
UMR7654, Palaiseau, Ile-de-France, France;
Université Paris Cité - Inserm UMR-S1124,
Paris, Ile-de-France, France.

Email: benoit.schneider@polytechnique.edu

## Abstract

Alzheimer's disease (AD) is the most common dementia in humans that today concerns 50 million individuals worldwide and will affect more than 100 million people in 2050. Except for familial AD cases (<5% of AD patients) for which AD pathology connects to mutations in critical genes involved in the processing of the amyloid precursor protein into neurotoxic Aß peptides, it remains unknown what provokes the overproduction and deposition of Aß peptides in the brain of sporadic AD cases (>95% of AD patients). Some nanosized materials, e.g., nanoparticles (NPs), are suspected of playing a role in the growing incidence of AD, due to their reactivity with biological systems, easiness of crossing physiological barriers, capacity to reach the central nervous system and accumulate in the brain. Incriminated NPs are the ultrafine air-borne particulate matter and manufactured NPs, such as titanium dioxide (TiO₂) NPs widely used in food and cosmetic industries or carbon black (CB) NPs used in rubber and as black pigment. Both TiO₂- and CB-NPs display neurotoxicity, but the mechanisms by which those NPs affect neuronal homeostasis and place neurons on the path to degeneration are unknown.

Combining *in vitro* and *in vivo* approaches, we provide prime evidence that TiO<sub>2</sub>- and CB-NPs bind a plasma membrane neuronal receptor, the cellular prion protein PrP<sup>C</sup>, well-known for its implication in prion diseases, and corrupt PrP<sup>C</sup> signaling activity. Dysregulation of PrP signaling by TiO<sub>2</sub> - or CB-NPs pomotes the NADPH oxidase-mediated overproduction of reactive oxygen species that alter neuronal redox equilibrium and the activation of 3-phosphoinositide-dependent kinase 1, at the root of an increased vulnerability of NP-exposed neurons to inflammation and the overproduction of neurotoxic Aβ peptides. By showing that neuronal exposure to some TiO<sub>2</sub>- and CB-NPs induce molecular signs of AD, these mechanistic data provide new insight into how human exposure to some engineered and environmental NPs may predispose to neurodegenerative diseases.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

© 2024 The Alzheimer's Association. *Alzheimer's & Dementia* published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
Identifying the mechanisms by which nanoparticles and other pollutants alter neuronal homeostasis would enable the generation of a database of pollutant-associated Adverse Outcome Pathways and provide clues for counteracting the adverse effects of those pollutants on the central nervous system.