DMSP for 'Quantitative Assessment of Nanoplastics in Alzheimer's Disease Brain and Their Role in Amyloid-β Aggregation'

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by extracellular amyloid-β (Aβ) plaque deposition and intracellular tau aggregation. While AD pathogenesis is shaped by both genetic and environmental factors, environmental exposures that modify AD pathology remain poorly defined. One emerging environmental factor is nanoplastic pollution. Nanoplastics are generated through the degradation of plastic waste into micro- and nanoscale particles and, due to the widespread use of plastics, are now ubiquitous in the environment and present in drinking water and food, leading to pervasive human exposure. Recent studies have detected nanoplastics in multiple human tissues, including the brain, and have reported increased nanoplastic burden in postmortem AD brains.Our previous work has demonstrated that polystyrene nanoplastics can directly interact with α-synuclein, an amyloidogenic protein associated with Parkinson’s disease, and accelerate its aggregation both in vitro and in animal models, raising the possibility that nanoplastics may similarly interact with other amyloidogenic proteins. Consistent with this idea, we have shown that polystyrene nanoplastics directly interact with Aβ peptide and significantly accelerate Aβ aggregation in vitro. In addition, we have demonstrated that orally ingested polystyrene nanoplastics can enter the mouse brain, establishing a potentially physiologically relevant exposure route linking nanoplastic exposure to neuropathology. However, progress in defining the role of nanoplastics in AD has been limited by the lack of analytical methods capable of sensitive and quantitative detection of nanoplastics in human brain tissue, and recent debates have raised concerns that previously reported brain nanoplastic levels may be confounded by lipid contamination. To address this technical gap, the proposed study will utilize a recently developed technique, flame-assisted atmospheric pressure chemical ionization mass spectrometry (FAPCI-MS), which enables rapid, preparation-free detection of polymer-specific fragment ions with high sensitivity in complex biological samples. By combining highly sensitive quantitative detection of nanoplastics in postmortem human brain tissue with mechanistic testing in animal models, we will test the central hypothesis that that environmentally relevant nanoplastics exposure exacerbate AD pathology by enhancing Aβ aggregation and increasing insoluble Aβ burden. Specifically, we will: 1) apply FAPCI-MS to quantitatively measure nanoplastic burden in healthy control and AD human brain tissue; and 2) determine whether chronic oral exposure to polystyrene nanoplastics promotes Aβ aggregation in mouse model through preferential association with insoluble Aβ assemblies. This project will provide a foundation for understanding the potential role of nanoplastics-an emerging environmental pollutant-in the pathogenesis of AD.