Microglial Clearance of Alzheimer's Amyloid-Beta Obstructed by Nanoplastics.

Microglial Clearance of Alzheimer’s Amyloid-Beta Obstructed by Nanoplastics - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Search Log in Primary site navigation Search Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Environ Sci Nano . Author manuscript; available in PMC: 2026 Jun 1. Published in final edited form as: Environ Sci Nano. 2025 May 6;12(6):3247–3260. doi: 10.1039/D5EN00291E Microglial Clearance of Alzheimer’s Amyloid-Beta Obstructed by Nanoplastics Yue Wang 1, 2 , Gangtong Huang 3 , Xiufang Liang 1, 2 , Nicholas Andrikopoulos 4, 5 , Huayuan Tang 6 , Feng Ding 3 , Pu Chun Ke 7 , Yuhuan Li 7, 8 Author information Article notes Copyright and License information 1 School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510006, China 2 Nanomedicine Center, The Great Bay Area National Institute for Nanotechnology Innovation, 136 Kaiyuan Avenue, Guangzhou, 510700, China 3 Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, USA 4 Department of Materials Science and Engineering, Monash University, Clayton, VIC 3800, Australia 5 ARC Training Centre for Cell and Tissue Engineering Technologies, Monash University, Clayton, VIC 3800, Australia 6 Department of Engineering Mechanics, Hohai University, Nanjing 211100, China 7 Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia 8 Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, 200032, China Author Contributions PCK, YW and YL conceived the project. YW, NA and XL performed TEM and BCA experiments. YW performed cell culture, confocal fluorescence microscopy, flow cytometry, ROS, mRNA expression, western blotting, proteomics, and data analyses. GH, HT and FD conducted computer simulations and data analysis. YW and YL prepared the figures. YW and PCK wrote the manuscript. PCK, YW, and YL edited the manuscript. ✉ Corresponding Authors Feng Ding, fding@clemson.edu ; Pu Chun Ke, pu-chun.ke@monash.edu ; Yuhuan Li, li.yuhuan1@zs-hospital.sh.cn Issue date 2025 Jun 1. PMC Copyright notice PMCID: PMC12162090  NIHMSID: NIHMS2084189  PMID: 40520627 The publisher's version of this article is available at Environ Sci Nano Abstract Understanding the neurological impact of nanoplastic exposure has become an area of intensive research recently. This study examined the molecular and cellular mechanisms of how nanoplastics affect amyloid-beta (Aβ) clearance by microglia in the context of Alzheimer’s disease (AD). Transmission electron microscopy and molecular dynamics simulations showed that polystyrene nanoplastics accelerated Aβ aggregation by forming a protein corona, promoting peptide fibrillization through hydrogen bonding and π-π interactions. Flow cytometry and endocytosis inhibition assays revealed that polystyrene nanoplastics impaired microglial uptake of Aβ while increasing their own cellular internalization, leading to microglial energy depletion and allowing Aβ aggregates to evade immune clearance. Additionally, proteomic analysis indicated that polystyrene nanoplastics disrupted microglial homeostasis, exacerbated neuroinflammation and metabolic dysregulation, and impaired the signalling pathway of ABC transporters critical for Aβ clearance in the AD brain. These findings suggest that nanoplastics contribute to AD pathology by impeding Aβ clearance and corrupting neuroimmune defense. Keywords: amyloid beta, Alzheimer’s disease, nanoplastics, microglia, uptake, protein corona Graphical Abstract Amyloid beta spontaneously rendered a protein corona on the nanoplastic surface, hindering clearance of the peptide by microglia and ABC transporters to amplify neuroimmune dysfunction and Alzheimer’s pathology. Introduction Plastic particulates are emerging environmental pollutants resulting from plastic degradation via radiation, abrasion, and microbial activity. 1 , 2 Due to their small size and physical, chemical and biological surface modifications, micro- and nanoplastics can gain mobility and bioavailability to infiltrate ecosystems and accumulate in living organisms. 3 , 4 Accordingly, addressing the environmental and health implications of micro- and nanoplastics has become an area of intensive research in recent years. Humans of today are constantly exposed to plastics through inhalation of airborne particles, ingestion of contaminated food and water, and dermal contact. 5 – 7 Indeed, micro- and nanoplastics have been found to log in human lungs, bloodstream, placenta, and brain tissue, 6 , 8 , 9 raising concerns about their systemic effects. Once inside the body, micro- and nanoplastics can translocate across the gastrointestinal epithelium, pulmonary alveoli, and the blood-brain barrier, reaching various compartments and organs to exert local and distal effects. 5 , 10 , 11 Exposure to plastic particulates is linked to the generation of reactive oxygen species (ROS), oxidative stress, inflammation, and organ damage. 12 – 14 In aquatic and mammalian models, plastic particulates have been shown to impair cellular metabolism, induce mitochondrial dysfunction, and disrupt immune responses. 12 , 15 , 16 Additionally, recent studies have revealed that plastic particulates can accumulate in the brain, impairing neurotransmission, inhibiting acetylcholinesterase activity, and triggering neurodegeneration. 5 , 9 , 17 – 19 Anionic nanoplastics, specifically, can harness the paracellular space of cerebral vasculature by disrupting adherens junctions 20 and promote the aggregation and gut-to-brain spread of α-synuclein in Parkinson’s models. 21 – 23 Given the prevalence and biological invasiveness of nanoplastics and in consideration of the rising global burden of dementia, it is urgent to understand the neurological implications of nanoplastic exposure. In this study, accordingly, we examined microglial uptake of polystyrene (PS) nanoplastics and amyloid beta (Aβ), whose extracellular amyloid accumulation is a hallmark of Alzheimer’s disease (AD). 24 , 25 Being relatively hydrophobic, monomeric Aβ displays a propensity for cell membrane, which facilitates the peptide’s self-assembly into toxic oligomers and amyloid fibrils over time. 26 Microglia serve as surveillance cells in the central nervous system (CNS), clearing pathogens—including Aβ plaques—through phagocytosis as part of the brain’s defense against endogenous and exogenous insults. Specifically, PS nanoplastics accelerated Aβ aggregation via the formation of a protein ‘corona’ 27 and hindered microglial uptake of Aβ, leading to immune evasion and increased burden of Aβ aggregates. On the molecular level, our proteomic analysis indicates that PS nanoplastics exacerbated neuroinflammation and metabolic dysregulation while downregulating the expression of ATP-binding cassette (ABC) transporters essential for Aβ clearance in the AD brain. 28 Together, this study suggests that nanoplastics suppressed neuroimmune defense by competing with Aβ for microglial uptake, thereby promoting Aβ toxicity and accelerating AD progression. Materials and methods Transmission electron microscopy (TEM) Aβ 42 powder (DAEFRHDSGYEVHHQKLVF FAEDVGSNKGAIIGLMVGGVVIA, purity>95%) was obtained from QYAOBIO (ChinaPeptides Co., Ltd.). To remove existing aggregates, the Aβ powder was completely dissolved in hexafluoro-2-propanol (Sigma-Aldrich, USA) overnight at room temperature. The Aβ stock was freeze-dried with a lyophilizer for future experiments. Aβ (25 μM) was incubated with or without PS nanoplastics (0.2 mg/mL) in Milli-Q water for 0 h and 24 h at 37 °C. All samples (10 μL) were diluted two times and deposited onto copper grids, where they were left to stand for 20 min. Excess liquid was carefully removed with filter paper. Samples were stained with a 4% aqueous phosphotungstic acid (Sigma Aldrich, USA) solution (neutral pH) for 1 min and 30 s. Excess dye was removed using filter paper, and the grids were gently washed twice with 20 μL of Milli-Q water. The grids were allowed to dry at room temperature, and images were obtained using an HT7800 TEM instrument (Hitachi, Japan). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) Aβ (100 μM) was incubated in PBS with or without nanoplastics (0.4 mg/mL) at 37 °C for 72 h. Following incubation, samples were mixed with SDS loading buffer (Beyotime, China) and boiled at 95 °C for 10 min to denature and detach Aβ from nanoplastics. Afterwards, the samples were centrifuged at 15,000 g for 5 min to remove nanoplastics. The supernatants were collected and loaded onto 12% SDS-PAGE gels (Yeason, China) at 180V for separation. A protein ladder (~6.5–240 kDa, Beyotime, China) was used to indicate molecular weights. Computational analysis All simulations were conducted using atomistic discrete molecular dynamics (DMD), 29 a unique molecular dynamics (MD) algorithm with significantly enhanced conformation sampling efficiency. The inter-atomic interactions, which were modeled with continuous potential functions in conventional MD methods, were instead modeled with discretized stepwise functions in DMD. The stepwise potentials were adopted from Medusa force field, and the solvent effects were modeled using implicit solvent model. Anderson’s thermostat was used to maintain the temperature of the simulation systems. DMD simulations have been extensively used in previous studies of protein-protein as well as protein-nanomaterial interactions. 30 The starting conformation of Aβ was based on a structure obtained with solution NMR (PDB ID: 1IYT). 31 The PS nanoplastic model with 100 repeating units was constructed with CHARMM GUI. 32 , 33 Then, the structure of the PS nanoplastic was relaxed by performing replica-exchange DMD (rexDMD) simulations in 16 trajectories with temperatures evenly distributed in the range of 275–425 K and an accumulative simulation time of 800 ns. The most compact PS nanoplastic structure, i.e., the snapshot with the smallest radius of gyration, under the lowest temperature (275 K) was chosen as the nanoplastic structure for all subsequent simulations. The diameter of the PS nanoplastic was approximately 4 nm. To ensure a consistency between the DMD simulations and the experiments, the nanoplastic surface was modified with hydroxyl ligands. Two series of DMD simulations were performed to investigate the interactions of the nanoplastic with an Aβ monomer and a dimer, respectively. For the Aβ monomer-PS simulations, an Aβ peptide and a PS nanoplastic were randomly positioned in a 12×12×12 nm 3 simulation box with a minimum separation of 1.5 nm. For the Aβ dimer-PS simulations, two Aβ peptides and one PS nanoplastic were randomly positioned in a 12×12×12 nm 3 simulation box with a minimum separation of 1.5 nm. To reduce computational cost and improve efficiency, the PS nanoplastic was kept static, while the Aβ peptides were assigned randomized initial velocities and free to move. For each series of simulations, 25 independent trajectories each lasted 200 ns under 300 K, resulting in an accumulative simulation time of 5 μs. Following our previous studies, 34 a contact was considered to form when the minimum heavy atom distance between an amino acid residue and the PS nanoplastic or two amino acid residues was shorter than 6.5 Å. Cell culture HMC3 (Human Microglial Clone 3) cells were obtained from Pricella Life Science and Technology (China) and cultured in Minimum Essential Medium (MEM, Gibco, USA) supplemented with 10% fetal bovine serum (Gibco, USA) and 1% penicillin-streptomycin. The cells were cultivated under standard conditions (37 °C, 5% CO 2 ) and passaged using trypsin (Gibco, USA) at 70–80% confluence. The total number of cell passages used in each experiment was less than fifteen. Interference of Aβ internalization by PS nanoplastics HMC3 cells (2.5×10 6 cells/well) were seeded in 6-well plates and cultured for 8 h. FITC-Aβ (25 μM) with PS nanoplastics (0.1, 0.2, or 0.4 mg/mL) or FITC-Aβ (25 μM) with red fluorescently-labeled PS nanoplastics (0.4 mg/mL) were incubated with the cells for 24 h. The cells were collected using trypsin without EDTA (0.25%), washed with warm 1×PBS three times in the dark. Internalized FITC-Aβ or fluorescently-labeled PS nanoplastics was quantified using a flow cytometer (Agilent, USA). Cytotoxicity assays of endocytosis inhibitors Cells were harvested after 2 h incubation with the above endocytosis inhibitors using trypsin (0.25%) without EDTA (Gibco, USA), then washed with PBS and centrifuged (1000 g , 5 min) three times. The cells were resuspended in 500 μL of PBS containing Annexin V-FITC (5 μL) and propidium iodide (5 μL, BD, USA). After 15 min of incubation in the dark, the extents of apoptosis and necrosis were quantified for the cells using a flow cytometer (Agilent, USA). Endocytosis activity HMC3 cells (2.5×10 6 cells/well) were cultured in 6-well plates overnight. Aβ (25 μM) and PS nanoplastics (0.1, 0.2, or 0.4 mg/mL) were added to the culture medium and incubated with the cells for 24 h. After discarding the culture medium and washing the cells with warm 1×PBS three times, a pHrodo ™ red zymosan bioparticles ™ conjugate kit (Thermo Fisher, USA) was used to test the cell endocytosis activities. The pHrodo bioparticles were dispersed in PBS to 200 μg/mL and sonicated for 10 min. The solutions were mixed with cells for 2 h at 37 °C. The cells were rinsed with PBS twice and the fluorescence intensities were quantified using flow cytometry. Fluorescence microscopy (Leica DMi 8, Germany) was employed to obtain images of the pHrodo bioparticles in the cells (Ex 560 nm/Em 585 nm). Real-time quantitative polymerase chain reaction (RT-qPCR) After 24 h treatment with Aβ (25 μM) and PS nanoplastics (0.2 mg/mL), total RNA was extracted from the cells using a MolPure Cell/Tissue Total RNA kit (Yeason, China) according to the manufacturer’s instructions. Hifair Advanced One Step RT-qPCR SYBR Green Kits (Yeason, China) were used for reverse transcription and the qPCR reactions. mRNA primer sequences are listed in Table S2 . Fluorescence signals were recorded and analyzed using a LightCycler ® 480 Instrument II (Roche, Switzerland). The mRNA expression of GAPDH was used to normalize target genes using the 2 −ΔΔCt method. Western blotting HMC3 cells (3×10 6 cells/well) were cultured in 6-well plates overnight. Aβ (25 μM) and PS nanoplastics (0.2 mg/mL) were added to the culture medium and incubated with the cells for 24 h. The cells were washed with PBS, collected with RIPA lysis buffer containing 1 mM PMSF for 30 min, and centrifuged at 3,000 rpm/4 °C for 10 min. Cell lysates were collected, and the amount of total protein was quantified using a BCA kit. The protein samples were mixed with SDS loading buffer (Beyotime, China) and boiled at 95 °C for 10 min before gel electrophoresis. The proteins were separated on 10% or 12% SDS-PAGE gels (Yeason, China) at 180V for 70 min and transferred to nitrocellulose membranes (Bio-rad, USA). After that, the membranes were blocked with rapid blocking buffer (MCE, USA) at room temperature for 10 min, then incubated with specific primary antibodies at 4 °C overnight. Relevant information about the antibodies is listed in Table S1 . After washing three times with 1×TBST solution, the membranes were incubated with corresponding secondary antibodies (1:10, 000, Absin, China) for 1 h at room temperature. The protein bands were visualized using an Enhanced Chemiluminescence (ECL) kit (Beyotime, China) and the iBright Imaging Systems (Thermo, USA). The band intensities were quantified using Image J (1.53c) software. Cell viability and intracellular ROS detection HMC3 cells (1×10 5 cells/well) were seeded in 96-well microplates. After attachment, the cells were treated with Aβ (25 μM) and PS nanoplastics (0.1, 0.2, or 0.4 mg/mL) for 24 h. The cells were then rinsed three times with 1×PBS and incubated with serum-free MEM medium containing 10% CCK-8 solution (Yeason, China) at 37 °C for 40 min. Absorbance at 450 nm was measured using a microplate reader (BioTek Synergy H1, USA). For ROS assays, 3×10 6 cells per well were seeded in 6-well plates overnight. Aβ (25 μM) and PS nanoplastics (0.4 mg/mL) were incubated with the cells for 24 h. 100 μM H 2 O 2 diluted in the medium was applied to simulate the cells for 2 h as a positive control. The cells were washed two times with warm 1×PBS. 2’−7’dichlorofluorescin diacetate (DCFH-DA, 5 μM) was prepared in serum-free MEM medium and incubated with the cells in the dark for 30 min. The cells were then rinsed with serum-free MEM medium thrice to remove excess probes, then collected with trypsin (0.25%, without EDTA). Next, the cells were washed with warm 1×PBS twice and their ROS production was evaluated using flow cytometry (Ex 488 nm/Em 525 nm). Proteomic analysis HMC3 cells (3×10 6 cells/well) were cultured in 6-well plates overnight and treated with Aβ (25 μM) and/or PS nanoplastics (0.2 mg/mL) for 24 h. After the standard protein extraction process, each sample was adjusted to the corresponding concentration. Samples were incubated with 400 mM Tris (2-carboxyethyl) phosphine (TECP, Sigma, USA) and 80 mM 2-Chloroacetamide (CAA, Sigma, USA) for reduction and alkylation at 60 ℃ for 30 min. The samples were mixed with an equal volume of ddH 2 O 2 and digested using sequencing-grade modified trypsin (Promega, USA) overnight at 37 ℃. Subsequently, trifluoroacetic acid (TFA, Sigma, USA) was added to the samples to a concentration of 1%. The supernatants of the samples were loaded onto an SDB-RPS column for desalination. After vacuum drying, the samples were stored at −20 ℃. The samples were then analyzed by an ion mobility-quadrupoletime of flight mass spectrometer (IM-Q-TOF MS) (Bruker timsTOF Pro, Germany). The reference was the human proteome database at the UniProt website. Statistical analysis Data were analyzed using GraphPad Prism 8 software and presented as mean ± standard deviation (SD). Significant differences among groups were determined using two-tailed Student’s t-tests, one-way or two-way analysis of variance (ANOVA) followed by Tukey’s post-hoc tests. Significance levels were set at * p < 0.05, ** p < 0.01, and *** p < 0.001 for comparisons with control. Significant differences between treatment groups were denoted as # p < 0.05, ## p < 0.01, and ### p < 0.001. Non-significant differences were denoted as n.s. Results and discussion Nanoplastic-Aβ interactions The morphologies of Aβ and PS nanoplastics at different time points were obtained by transmission electron microscopy (TEM). As shown in Fig. 1A , the nanoplastics were spherical with a diameter of ~50 nm. Rigid fibrils were observed after incubating Aβ monomers at 37 °C for 24 h. In comparison, the presence of nanoplastics led to the formation of more numerous and thinner fibrils, as surface-bound Aβ acted as nucleation seeds, accelerating fibrillization. A sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) assay revealed that PS nanoplastics promoted peptide aggregation, resulting in the dimers, trimers, tetramers, and higher molecular weight Aβ species ( Fig. 1B & C ). The enhanced aggregation kinetics may be attributed to the Aβ ‘corona’ adsorbed onto the nanoplastic surface, where a high local concentration of Aβ facilitated conformational changes and intermolecular interactions with free Aβ peptides in solution. 35 This protein corona formation was quantified by measuring Aβ depletion in the supernatant. Nanoplastics exhibited a strong adsorption capacity, as evidenced by a reduction in Aβ concentration in the supernatant by 51.9%, 66.1%, and 68.1% after 1, 3, and 6 h of co-incubation, respectively ( Fig. S1A ). This time-dependent Aβ adsorption indicates rapid corona formation within 1 h, reaching equilibrium by 6 h, consistent with typical nanoparticle-protein corona dynamics. 36 In addition, confocal fluorescence images also revealed clear co-localization of nanoplastics and Aβ in human microglial clone 3 (HMC3) cells ( Fig. S1B & C ), making connections with cerebral immune defense and the accumulation of the synthetic and peptide species. Fig. 1. Interactions between PS nanoplastics and Aβ. Open in a new tab (A) TEM images of Aβ incubated with or without nanoplastics in water for 0 and 24 h at 37 °C. (B-C) SDS-PAGE analysis of Aβ incubated with PS nanoplastics at 37 ℃ for 72 h. (B) A representative SDS-PAGE gel image. (C) Statistical analysis of the Aβ species (n=3). Data were analyzed using two-tailed Student’s t-tests. * p < 0.05, ** p < 0.01 represent significant differences and n.s. represents no significant difference. (D) The contact probability of each residue of an Aβ monomer with a PS nanoplastic is shown on the left. This residue-wise contact probability is also mapped onto the Aβ monomer structure, with blue to red corresponding to minimal and maximal contact probabilities, respectively. A representative snapshot of Aβ-nanoplastic binding is shown on the right. Hydrogen bonds and π-π interactions between the Aβ monomer and the nanoplastic are magnified and highlighted in yellow and blue, respectively. (E) Time evolution of the distances between two Aβ peptide chains and one PS nanoplastic of a representative trajectory. Snapshots at timepoints of 0, 50, 120, and 200 ns, indicated by red arrows, are shown above. The two Aβ peptide chains are colored blue and orange, respectively, both in the distance-time graph and the snapshots. (F) Inter-chain contact map between the Aβ monomers with and without the PS nanoplastic is shown on the left. The parallel in-register β-sheet pattern is highlighted with a red dashed box. A representative snapshot is shown on the right, where the nanoplastic is represented as spheres and the Aβ peptides as cartoons. The C-terminal parallel in-register β-sheets between the two Aβ peptides, corresponding to those highlighted in the box of the contact map, are shown in orange and blue for the separate chains. To elucidate the molecular details of Aβ-nanoplastic interactions, we performed atomistic discrete molecular dynamics (DMD) simulations of an Aβ peptide binding to a PS nanoplastic with hydroxyl surface modifications. The plateaus in the time evolution of average secondary structure and energy indicate that the simulation systems had reached equilibrium ( Fig. S2A ). To investigate contributions of the different regions of Aβ to nanoplastic binding, the contact probability of each peptide residue with the nanoplastic was calculated ( Fig. 1D ). Specifically, the peptide N-terminus interacted via its polar residues (ARG, HIS, VAL) with the nanoplastic hydroxyl groups to render hydrogen bonding. In addition, the aromatic residues (PHE, HIS, TYR) of the peptide N-terminus and the nanoplastic benzene rings established π-π interactions to reinforce their binding. A representative snapshot extracted from the DMD simulation exemplifies these key interactions ( Fig. 1D ). To further elucidate the formation of Aβ corona on the nanoplastic surface, simulations of two Aβ peptides in the presence and absence of a PS nanoplastic were performed ( Fig. 1E , F ). An Aβ corona formed on the nanoplastic surface, as revealed by simulation snapshots and changes in the distances between the two Aβ peptides and the nanoplastic over time ( Figs. 1E , S2B ). As the N-termini of the peptides bound to the nanoplastic, the Aβ dimer exhibited a high propensity to form parallel in-register β-sheets compared with the Aβ homodimer formed alone, as evidenced by the inter-chain contact map and residue-wise secondary-structure content plot ( Figs. 1F , S2C ). Taken together, our simulations corroborated the experimental data and further uncovered the molecular mechanism of corona formation and enhanced amyloid aggregation of Aβ with nanoplastics. Strong N-terminal binding, driven by hydrogen bonding and π-π interactions, led to local Aβ enrichment on the nanoplastic surface, while the peptide’s C-terminal region initiated amyloid fibril nucleation. The nanoplastic–Aβ corona complexation likely altered endogenous cellular uptake behavior and other biological processes, 37 as we will reveal in the latter sections. Nanoplastics assisted the immune escape of Aβ from microglia Previous studies have shown that nanoplastics can induce abnormal activation and toxicity in microglia. 38 However, the interaction between PS nanoplastics and Aβ within the context of innate immune response, especially under non-physiological conditions, remains unknown. To investigate how nanoplastics interfere with Aβ clearance and their related molecular and cellular mechanisms, we treated HMC3 cells with Aβ (25 μM) and different concentrations of PS nanoplastics (0.1, 0.2, or 0.4 mg/mL) for 24 h. Compared with Aβ alone, co-treatment with increasing concentrations of PS nanoplastics significantly reduced Aβ uptake by microglia in a dose-dependent manner, suggesting that nanoplastics hindered the microglial clearance of Aβ ( Fig. 2A & B ). Conversely, Aβ promoted cellular internalization of PS nanoplastics compared to nanoplastics alone ( Figs. 2C & D and S3 ). Specifically, with the treatment of Aβ (25 μM) + PS (0.4 mg/mL), cellular uptake of Aβ was inhibited by 51.5% compared with Aβ (25 μM), while internalization of PS nanoplastics was elevated by 10.4% compared with nanoplastics alone ( Figs. 2C & D and S3 ). These findings suggest that nanoplastics cooperated with pathogenic proteins to evade immune detection. Fig. 2. PS nanoplastics interfered with Aβ clearance by microglia. Open in a new tab (A, B) After treatment with FITC-labeled Aβ (25 μM) or PS nanoplastics (0.1, 0.2, or 0.4 mg/mL) for 24 h, the intracellular fluorescence of Aβ was quantified by flow cytometry. Overlay histograms (A) and statistical analysis (B) of intracellular Aβ fluorescence in HMC3 cells (n = 3). (C, D) HMC3 cells were treated with fluorescently-labeled PS nanoplastics (0.4 mg/mL) or FITC-labeled Aβ (25 μM) for 24 h (n = 3). Overlaid histograms (C) and statistical analysis (D) of PS nanoplastic fluorescence in HMC3 cells. (E, F) Endocytic pathways of FITC-PS nanoplastics and FITC-Aβ into HMC3 cells were explored utilizing various endocytosis inhibitors. HMC3 cells were pre-treated with 5 mM MβCD, 30 μM EIPA or 10 μM MDC for 2 h, respectively. The cells were then exposed to FITC-PS nanoplastics (0.2 mg/mL) or FITC-Aβ (25 μM) for 3 h. Percentages of positive cells of PS (E) and Aβ (F) were quantified by flow cytometry. The inhibition of endocytosis was independent of cell death. (G) HMC3 cells were treated with MβCD (5 mM), EIPA (30 μM), or MDC (10 μM) for 2 h. The proportion of normal cells was determined by flow cytometry (n = 3). (H) Statistical analysis of panel (G). To further elucidate the mechanisms of Aβ and nanoplastic cellular internalization, we investigated their uptake pathways using various endocytosis inhibitors. MDC and MβCD suppress caveolin-dependent and clathrin-mediated endocytosis, 39 , 40 respectively, while EIPA blocks macropinocytosis. 41 After 3 h exposure to PS nanoplastics, the percentage of positive cells increased to 26.7% ( Fig. 2E ). With 2 h of pre-administration, 30 μM EIPA and 5 mM MβCD significantly reduced the proportion of PS-positive cells by 6.4% and 8.2%, respectively, indicating that the HMC3 cells internalized nanoplastics via clathrin-mediated and macropinocytosis pathways ( Figs. 2E & S4 ). Similarly, Aβ was primarily internalized through macropinocytosis, as EIPA (30 μM) limited the portion of Aβ-positive cells by 14.4% ( Figs. 2F & S5 ). Meanwhile, no significant apoptosis or necrosis was detected following the endocytosis inhibitor treatments, confirming the uptake inhibition was not due to cell death ( Fig. 2G & H ). It is noteworthy that macropinocytosis is a shared, energy-dependent mechanism for the cell entry of both Aβ and the nanoplastics, suggesting a competitive uptake taking place between Aβ and the nanoplastics. Nanoplastic and Aβ synergistically disrupted cellular homeostasis The function of microglia is essential for maintaining CNS homeostasis, and their impaired activity can directly impact the rate of Aβ elimination. 42 Here, upon removal of PS nanoplastics and Aβ, the endocytosis activity of HMC3 cells was evaluated by quantifying the internalization of pHrodo-Red labeled particles. HMC3 cells were pre-treated with PS nanoplastics or Aβ for 24 h and then the medium was replaced with a pHrodo-red particle suspension. While individual PS treatment exerted a minimal impact on HMC3 cells, Aβ reduced cellular endocytosis by 18.7% ( Fig. 3A – C ). Moreover, Aβ and PS nanoplastics at 0.1, 0.2, or 0.4 mg/mL concentrations synergistically reduced microglial endocytosis by 21.0%, 34.7%, or 46.0% ( Fig. 3A – C ), respectively, indicating a suppressed endocytosis activity of HMC3 cells by the peptide-nanoplastic co-treatment, in a nanoplastic dose-dependent manner. In addition, the expression of allograft inflammatory factor 1 (AIF-1) in microglia, which regulates phagocytosis via modification of actin bundling, 43 was measured. The result revealed a consistent trend. Compared with the treatment of nanoplastics or Aβ alone, the protein expression of AIF-1 was significantly diminished with the co-treatment of PS nanoplastics and Aβ ( Fig. 3D & E ). The addition of nanoplastics not only reduced internalization of Aβ but also hampered endocytosis of microglia in the presence of Aβ to ensure a vicious cycle. 44 In literature, abnormal accumulation of Aβ has been found to be accompanied by a pro-inflammatory response. 45 Indeed, our RT-qPCR assay revealed that nanoplastics and Aβ co-treatment drove microglia towards a pro-inflammatory response characterized by an increased expression of pro-inflammatory markers iNOS and TNF and decreased anti-inflammatory cytokines IL-10 and Arg-1 ( Fig. 3F ). The level of ROS ( Fig. 3G & H ) and the rate of cell death ( Fig. 3I ) in the co-treatment group (Aβ: 25 μM; nanoplastics: 0.4 mg/mL) were higher than that of the groups treated with Aβ or PS nanoplastics alone ( Fig. 3I ). This can be attributed to a significant increase in the intracellular accumulation of PS nanoplastics in the co-treatment group ( Fig. 2C – D ), 46 which favored cellular ROS production ( Fig. 3G & H ) and an elevated energy/ATP consumption by endocytosis. 47 Collectively, nanoplastics exacerbated microglial dysfunction, evidenced by impaired phagocytic activity, enhanced Aβ-induced pro-inflammation, and increased ROS levels and cell death rate. Fig. 3. Nanoplastics synergized with Aβ to exacerbate microglial endocytosis activity and defensive response. Open in a new tab (A) After treatments with PS nanoplastics (0.1, 0.2, or 0.4 mg/mL) for 24 h in the presence or absence of Aβ (25 μM), cell culture medium was replaced with a pHrodo-Red labeled particle suspension to evaluate the endocytosis activity of microglia. The mean pHrodo-red fluorescence intensity in the cells was acquired by flow cytometry (n = 3). (B) Statistical analysis of pHrodo-red fluorescence intensity in HMC3 cells. (C) Representative fluorescence microscopy images of cells after the treatment of PS nanoplastics with or without Aβ, followed by incubation with pHrodo-Red labeled particles (n = 3). Scale bar: 100 μm. (D-F) Cells were treated with Aβ (25 μM) or PS nanoplastics (0.2 mg/mL) for 24 h. (D, E) Western blot detection and statistical analysis of AIF-1 protein expression (n = 3). (F) mRNA expression of pro-inflammatory mediators (iNOS and TNF) and anti-inflammatory mediators (IL-10 and Arg-1) (n = 3). (G, H) Cellular ROS detection. (G) HMC3 cells were treated with nanoplastics (0.4 mg/mL), or Aβ (25 μM) for 24 h. Cells pretreated with 100 μM H 2 O 2 diluted in the medium for 2 h served as a positive control. (H) Statistical analysis of panel (G). (I) HMC3 cells viability tests (n = 4). Data are shown as mean ± SD and were analyzed using one-way ANOVA, followed by Tukey’s post-hoc tests. * p < 0.05, ** p < 0.01, *** p < 0.001 represent significant differences compared with the control, #p < 0.05, ###p < 0.001 represent significant differences between treatment groups, and n.s. represents no significant difference. To explore the preferential cellular uptake of PS nanoplastics and the phenomenon of Aβ immune escape, we conducted the following analysis. First, both PS nanoplastics and Aβ utilized macropinocytosis as a common internalization pathway, indicating a competitive endocytosis process within HMC3 cells. Second, microglia employed additional clathrin-mediated endocytosis for PS nanoplastics, which explains their preferential uptake by HMC3 cells. PS nanoplastics accelerated the aggregation of Aβ peptides, leading to the formation of larger Aβ aggregates ( Fig. 1A – C ). This increased aggregation increased the time and energy needed for lipid bilayer wrapping, resulting in reduced cellular uptake. 48 , 49 The increased cellular uptake of PS nanoplastics in the presence of Aβ can be attributed to the formation of an Aβ protein ‘corona’ on the nanoplastic surface, 50 as supported by the adsorption and co-localization data ( Fig. S1A – C ). The protein corona is known to dictate the biological fate of nanoparticles, including their cellular association and uptake. 51 , 52 The intracellular burden of nanoparticles, on the other hand, is crucial in eliciting their cellular response and toxicity. 46 Our findings suggest that the increased intracellular presence of nanoplastics, driven by the high membrane affinity of the Aβ corona, led to heightened dysfunction and cell death in HMC3 cells. In summary, our study revealed a positive correlation between nanoplastic exposure and evasion of Aβ from microglial clearance involving PS-mediated Aβ misfolding, competition for transmembrane transport, and amplification of nanoplastic toxicity through the Aβ corona. Polystyrene nanoplastics amplified Aβ-driven neuroimmune dysregulation A proteomic analysis of HMC3 cells was performed to further understand the molecular impact of their exposure to the peptide and the nanoplastics. A total of 161 differentially expressed proteins (|log 2 fold change| > 0.585, p -value < 0.05) were detected across the nanoplastics, Aβ, and their co-treatment ( Fig. 4A ), in relation to endocytosis (e.g., DGKQ, ELMO3, CBLB), inflammation (e.g., THEM4, C5, C6, C7, C9, A1BG, IKKB, C4A), lipid (e.g., APOE, APOA4, APOC3) and cell homeostasis (e.g., LZTS2, CCND2, UQCC3, LYPLA2, TFAP4, KRT16, FERMT3, TGFBI, CLEC11A ALDH1L1). The Venn diagram highlights 7 overlapping protein signatures across the treatment groups ( Fig. 4B ), among which six (C4A, C5, C9, A1BG, C7, and C6) were identified as being involved in complement activation and immune-related processes ( Fig. 4C & D ). Microglia-mediated innate immunity plays an indispensable role in the pathogenesis of AD, and existing evidence has implicated inflammatory cytokines as positively correlated with the production of Aβ. 53 Both the peptide and the nanoplastics disturbed complement system and immune responses, which entailed their significant pro-inflammatory capacity (the increased levels of INOS and TNF) and compromised Aβ clearance by microglia, corresponding to the results described above ( Figs. 2A , B & 3F ). Fig. 4. Liquid chromatography–mass spectrometry (LC–MS) based proteomic analysis of HMC3 cells exposed to Aβ or PS nanoplastics. Open in a new tab The cells were incubated with Aβ (25 μM) or PS nanoplastics (0.2 mg/mL) for 24 h. The protein expression profiles of cells were identified by LC-MS (n = 3). (A) Heatmap of differentially expressed proteins. Proteins that met the conditions of |log 2 fold change| > 0.585 and p -value < 0.05 were considered significantly different. (B) Venn diagram visualized overlapping differentially expressed proteins among the PS vs. control, Aβ vs. control, and Aβ+PS vs. control groups. (C) Protein interaction network of C4A, C5, C9, A1BG, C7, and C6 from the STRING database. (D) GO-enrichment analysis of the proteins in panel (C). (E) KEGG enrichment analysis of top 15 terms across various treatment groups (PS vs. control, Aβ vs. control, Aβ+PS vs. control, Aβ + PS vs. Aβ and Aβ + PS vs. PS). The dot sizes represent the numbers of enriched proteins. (F-G) ABC transporters pathway was examined with gene set enrichment analysis in PS vs. control and Aβ vs. control groups. NES: normalized enrichment score. Additional KEGG pathway enrichment analysis found that the differentially expressed proteins were related to human nervous system diseases (amyotrophic lateral sclerosis, AD, Huntington’s disease), cellular processes (endocytosis, regulation of actin cytoskeleton, cellular senescence), and metabolism pathways ( Fig. S7 ). The differentially regulated proteins in the PS nanoplastics, Aβ, and Aβ + PS treatment groups were involved in multiple overlapping pathways ( Fig. 4E ). Specifically, they were highly related to the pathogenesis of AD and were pertinent to the PI3K-AKT pathway, 54 MAPK pathway, 55 complement and coagulation cascades, 56 as well as neuroactive ligand receptor interactions. 57 A recent study showed that, upon exposure to environmental stimuli, microglial metabolic reprogramming mediated dysfunction and cell homeostasis further affecting the cognition of AD mice. 58 In this study, a comparison of the Aβ + PS and Aβ groups showed that the peptide-nanoplastic co-treatment disturbed metabolic signaling pathways ( Fig. 4E ), particularly those related to fat digestion and absorption, glycerolipid metabolism, glycerophospholipid metabolism, insulin signaling, the phosphatidylinositol signaling system, and vitamin digestion and absorption. These pathways are related to AD pathogenesis, metabolism, and cellular processes. Moreover, significant increases in apolipoprotein E4 (APOE4) and diacylglycerol kinase alpha (DGKA) expression, both of which associated with AD risks, 59 , 60 were observed with western blots after Aβ + PS treatment compared to Aβ ( Fig. S8 ). Moreover, we noted that both PS nanoplastics and Aβ inhibited the ABC transporters pathway ( Fig. 4F – G ), indicating a common mechanism for their synergistic effects impeding Aβ clearance. These results showed that a protein recruitment of AD-related pathways was launched after Aβ or nanoplastic treatment and nanoplastics may amplify the adverse effects of Aβ and promote the progression of AD through a crosstalk between dysregulated inflammation and metabolic pathways. Conclusion Extracellular deposition of Aβ in the brain is a hallmark of AD pathology. 61 In this study, we investigated the effects of nanoplastics, a pervasive environmental pollutant, on microglial sequestration of Aβ, a key function in cerebral immune defense against AD. Due to their small size and relatively hydrophobic surface, nanoplastics promoted Aβ aggregation through the form of a protein corona and competed with the peptide and its polymorphic aggregates for microglial uptake. This competition increased the extracellular accumulation of Aβ by raising the energy cost for internalization, thereby diminishing the capacity of microglia to clear the accumulating toxic aggregates. This consequently exacerbated microglial dysfunction, leading to heightened neuroinflammation, oxidative stress, and metabolic dysregulation—key factors implicated in AD pathogenesis. Notably, our proteomic analysis implicated nanoplastics in downregulating ABC transporters expression, reinforcing the notion that nanoplastics hinder Aβ clearance in AD. Given the widespread presence of nanoplastics in the environment and their documented ability to infiltrate the human body, 5 , 8 including the brain, 9 our study provided critical evidence that the interaction of nanoplastics with Aβ may serve as an environmental trigger for neurodegenerative diseases. This finding adds to the growing body of research linking environmental pollutants to neurological disorders and underscores the urgent need to assess the neurotoxic risks posed by nanoplastics. 11 , 20 – 23 , 62 By elucidating the molecular and cellular mechanisms through which nanoplastics impair microglial function, our study offers new insights into the potential role of such exogenous pollutants in AD etiology. These findings may aid in the development of future strategies against nanoplastic exposure to alleviate its impact on neurodegenerative disease and progression. Supplementary Material Supplementary Information NIHMS2084189-supplement-Supplementary_Information.pdf (4.3MB, pdf) Supporting information The Supporting Information is available free of charge. Adsorption assay ( Fig. S1 ); secondary structure, energy, and dynamics of the simulation systems ( Fig. S2 ); Aβ promoted microglial uptake of PS nanoplastic ( Fig. S3 ); microglial uptake of the nanoplastics ( Fig. S4 ) and Aβ ( Fig. S5 ); signal channel images of Fig. 3C ( Fig. S6 ); KEGG pathway enrichment analysis ( Fig. S7 ); western blot assays ( Fig. S8 ); antibodies ( Table S1 ); and primer sequences ( Table S2 ) used in the study. Acknowledgments This work was supported by National Key Research and Development Program (2022YFC2409700 and 2021YFA1200900, P.C.K.), Shanghai Magnolia Talent Plan Pujiang Project (No. 24PJA015, Y.L.), National Natural Science Foundation of China (12402237, H.T.), Natural Science Foundation of Jiangsu Province (No. BK20241505, H.T.), and National Institutes of Health (R35GM145409 and R01CA243001, F.D.). PCK acknowledges the Distinguished Visiting Scholar Program with the University of Macau. Footnotes Declaration of Competing Interest The authors declare no competing interests. Data Availability Statement The experimental data supporting the findings of this study are available as source data files. The computer simulation setup files, data for making the figure, and PyMOL sessions of protein structures are available at https://doi.org/10.5281/zenodo.15021639 . References 1. 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[ DOI ] [ PubMed ] [ Google Scholar ] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. Supplementary Materials Supplementary Information NIHMS2084189-supplement-Supplementary_Information.pdf (4.3MB, pdf) Data Availability Statement The experimental data supporting the findings of this study are available as source data files. The computer simulation setup files, data for making the figure, and PyMOL sessions of protein structures are available at https://doi.org/10.5281/zenodo.15021639 . 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