Amyloid precursor protein (APP) is directly related to Aβ amyloidosis—a hallmark of Alzheimer’s disease (AD). However, the impact of environmental factors upon APP biology and Aβ amyloid pathology have not been well studied. The increased use of nanoparticles (NPs) or engineered nanomaterials (ENMs) has led to a growing body of evidence suggesting that exposure to metal/metal oxide NPs, such as Fe2O3, CuO, and ZnO, may contribute to the pathophysiology of neurodegenerative diseases such as AD through neuroinflammation. Our previous studies indicated that exposure to CuO nanoparticles (CuONPs) induce potent in vitro neurotoxicity. Herein, we investigated the effects on APP expression in neuronal cells exposed to different metal oxide NPs. We found a low dose of CuONPs effectively activated the NFκB signaling pathway and increased APP expression. Moreover, the inhibition of p65 expression using siRNA abolished CuONP-mediated APP expression, suggesting that NFκB-regulated APP expression in response to CuONP exposure may be associated with AD pathology.

Alzheimer' s Disease (AD) affects at least 5.7 million Americans, and it is the sixth leading cause of death in the United States. At the onset, patients experience minor memory problems. Next, impairments in speech and motor function manifest as a limitation to well-being and independence. Slowing this pandemic rise is critical, since AD also bears a huge socioeconomical burden. Unfortunately, there is limited prevention and no effective cure has been found, as all clinical trials for promising AD drugs have failed thus far. The pathological hallmarks of AD include amyloid-β plaques (Aβ), neurofibrillary tangles (NFT), and neuroinflammation. Other factors include APOE4 and environmental stressors, such as metal dyshomeostasis, which contribute to AD pathogenesis. Herein, we review major contributing factors involved in AD pathophysiology. Deeper understanding of associated molecular mechanisms underlying AD pathogenesis is critical for developing novel AD theranostics.