Oral Exposure to Food‐Grade Nanoparticles Poses a Risk of Alzheimer's Disease‐Like Symptoms by Triggering Autophagy Defects in Neurons

Preliminary epidemiological studies have revealed a relationship between exposure to environment-related ultrafine particles and the escalation of Alzheimer's disease (AD). Oral exposure through food is a significant route of human contact with nanoparticles; however, the potential risk of AD induced by food-grade nanoparticles and the underlying mechanisms remain largely unclear. Here, this study reveals a common mechanism by which food-grade nanoparticles, including titanium dioxide, nanosilica, and nanosilver, trigger AD-like pathological changes through epigenetic alterations. Exposure to food-grade nanoparticles triggers changes in DNA methylation and aberrant ryanodine receptor-Ca²⁺ signaling in the mouse brain, contributing to lysosomal impairment and disrupted autophagic flux in neurons. Crucially, these autophagy defects reduced the ability to clear β-amyloid and pTau proteins, which ultimately accumulated and triggered spatial cognition and memory deficits in mice. In conclusion, this study elucidates the shared toxicological mechanisms induced by different food-grade nanoparticles, thereby offering valuable insights into ingested nanoparticle exposure and its potential association with neurodegenerative diseases.