Abstract
Introduction: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with limited treatments and poorly defined environmental risks. Micro- and nanoplastics (MNPs) are widespread pollutants linked to neurotoxicity, but their role in AD remains unclear. Methods: We investigated the effects of 90-day intragastric exposure to polystyrene nanoplastics (PS-NPs) in amyloid precursor protein/presenilin 1 (APP/PS1) mice using behavioral tests, brain imaging, histopathology, and cell-type-resolved proteomics. Results: PS-NPs exacerbated cognitive deficits and hippocampal damage in APP/PS1 mice. Proteomic and CellChat analyses revealed PS-NPs enhanced neuroglial communication through the collagen-integrin axis. In vitro triculture demonstrated that PS-NPs strengthened collagen-mediated astrocyte-microglia-neuron signaling, whereas in vivo blockade with TC-I 15 suppressed collagen activation and improved cognition in PS-NP-exposed APP/PS1 mice. Single-nucleus RNA sequencing of human AD brains validated conserved activation of collagen signaling. Discussion: Our findings highlight that PS-NPs exacerbate cognitive impairment in AD by driving collagen-dependent neuroglial dysfunction, establishing MNPs as modifiable environmental risk factors. Highlights: MNPs act as environmental risk factors that worsen cognitive impairment in AD. PS-NPs trigger glial-neuronal communication via the collagen-integrin axis in AD. PS-NP-induced astrocyte- and microglia-derived collagen, driving neurotoxicity in AD. TC-I 15 blocked collagen signaling and rescued cognition in PS-NP-exposed AD mice. Collagen signaling was upregulated in human AD brains, confirming disease relevance.