Nanoplastics trigger glial–neuronal collagen signaling miscommunication to exacerbate cognitive impairment in Alzheimer's disease

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.