With the prevalence of nanoplastics in daily life, human exposure is inevitable. However, whether and how nanoplastics cause neurotoxicity in humans remains obscure. Herein, we conducted a 28-day repeated dose oral toxicity study in C57BL/6 J mice exposed to 0.25-250 mg/kg body weight (BW) polystyrene nanoplastics (PS-NPs, 50 nm). We revealed that PS-NP-caused Parkinson's disease (PD)-like neurodegeneration in mice by multiple approaches. Furthermore, a single-nucleus RNA sequencing of 62,843 brain nuclei unearthed PS-NP-induced cell-specific responses in the mouse brains. These disturbed responses among various brain cells were primarily linked with energy metabolism disorder and mitochondrial dysfunction in all brain cells, and especially in excitatory neurons, accompanied by inflammatory turbulence in astrocytes and microglia, dysfunction of proteostasis and synaptic-function regulation in astrocytes, oligodendrocytes, and endotheliocytes. These responses may synergize in PS-NP-motivated PD-like neurodegeneration pathogenesis. Moreover, we verified these single-nucleus transcriptomics findings on different brain regions and found that PS-NPs potentially caused PD-like neurodegeneration primarily by causing energy metabolism disorder in the substantia nigra pars compacta (SNc) and striatum. This manifested as decreases in adenosine triphosphate (ATP) content and expression levels of ATP-associated genes and proteins. Given nanoplastics' inevitable and growing exposure risks to humans, the neurological health risks of nanoplastic exposure warrant serious consideration.

The widespread use of plastic products worldwide has brought about serious environmental issues. In natural environments, it's difficult for plastic products to degrade completely, and so they exist in the form of micro/nanoplastics (M/NPs), which have become a new type of pollutant. Prolonged exposure to M/NPs can lead to a series of health problems in humans, particularly toxicity to the nervous system, with consequences including neurodevelopmental abnormalities, neuronal death, neurological inflammation, and neurodegenerative diseases. Although direct evidence from humans is still limited, model organisms and organoids serve as powerful tools to provide important insights. This article summarizes the effects of M/NPs on the nervous system, focusing on cognitive function, neural development, and neuronal death. Mechanisms such as neurotransmitter synthesis and release, inflammatory responses, oxidative stress, the gut-brain axis, and the liver-brain axis are covered. The neurotoxicity induced by M/NPs may exacerbate or directly trigger neurodegenerative diseases and neurodevelopmental disorders. We particularly emphasize potential therapeutic agents that may counteract the neurotoxic effects induced by M/NPs, highlighting a novel future research direction. In summary, this paper cites evidence and provides mechanistic perspectives on the effects of M/NPs on neurological health, providing clues for eliminating M/NP hazards to human health in the future.

Microplastics (MPs), which are emerging environmental pollutants, remain uncertainties in their toxic mechanism. MPs have been linked to severe liver metabolic disorders and neurotoxicity, but it is still unknown whether the abnormal metabolites induced by MPs can affect brain tissue through the liver-brain axis. Exposed to MPs of chickens results in liver metabolic disorders and increased glutamine and glutamate synthesis. The relative expression of glutamine in the C group was -0.862, the L-PS group was 0.271, and the H-PS group was 0.592. The expression of tight junction proteins in the blood-brain barrier (BBB) was reduced by PS-MPs. Occludin protein expression decreased by 35.8%-41.2%. Claudin 3 decreased by 19.6%-42.3%, and ZO-1 decreased by 28.3%-44.6%. Excessive glutamine and glutamate cooperated with PS-MPs to inhibit the Nrf2-Keap1-HO-1/NQO1 signaling pathway and triggered autophagy-dependent ferroptosis and apoptosis. GPX protein expression decreased by 30.9%-38%. LC3II/LC3I increased by 54%, and Caspase 3 increased by 45%. Eventually, the number of Purkinje cells was reduced, causing neurological dysfunction. In conclusion, this study provides new insights for revealing the mechanism of nervous system damaged caused by PS-MPs exposed in chickens.

Oral ingestion is the primary route for human exposure to nanoplastics, making the gastrointestinal tract one of the first and most impacted organs. Given the presence of the gut-brain axis, a crucial concern arises regarding the potential impact of intestinal damage on the neurotoxic effects of nanoplastics (NPs). The intricate mechanisms underlying NP-induced neurotoxicity through the microbiome-gut-brain axis necessitate further investigation. To address this, we used mice specifically engineered with nuclear factor erythroid-derived 2-related factor 2 () deficiency in their intestines, a strain whose intestines are particularly susceptible to polystyrene NPs (PS-NPs). We conducted a 28-day repeated-dose oral toxicity study with 2.5 and 250 mg/kg of 50 nm PS-NPs in these mice. Our study delineated how PS-NP exposure caused gut microbiota dysbiosis, characterized by and proliferation, resulting in increased levels of interleukin 17C (IL-17C) production in the intestines. The surplus IL-17C permeated the brain via the bloodstream, triggering inflammation and brain damage. Our investigation elucidated a direct correlation between intestinal health and neurological outcomes in the context of PS-NP exposure. Susceptible mice with fragile guts exhibited heightened neurotoxicity induced by PS-NPs. This phenomenon was attributed to the elevated abundance of microbiota associated with IL-17C production in the intestines of these mice, such as and , provoked by PS-NPs. Neurotoxicity was alleviated by treatment with anti-IL-17C-neutralizing antibodies or antibiotics. These findings advanced our comprehension of the regulatory mechanisms governing the gut-brain axis in PS-NP-induced neurotoxicity and underscored the critical importance of maintaining intestinal health to mitigate the neurotoxic effects of PS-NPs.

Environmental plastic wastes are potential health hazards due to their prevalence as well as their versatility in initiating physical, chemical, and biological interactions and transformations. Indeed, recent research has implicated the adverse effects of micro- and nano-plastics, including their neurotoxicity, yet how plastic particulates may impact the aggregation pathway and toxicity of amyloid proteins pertinent to the pathologies of neurological diseases remains unknown. Here, electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS) is employed to reveal the polymorphic oligomerization of NACore, a surrogate of alpha-synuclein that is associated with the pathogenesis of Parkinson's disease. These data indicate that the production rate and population of the NACore oligomers are modulated by their exposure to a polystyrene nanoplastic, and these cellular assays further reveal an elevated NACore toxicity in microglial cells elicited by the nanoplastic. These simulations confirm that the nanoplastic-NACore association is promoted by their hydrophobic interactions. These findings are corroborated by an impairment in zebrafish hatching, survival, and development in vivo upon their embryonic exposure to the nanoplastic. Together, this study has uncovered the dynamics and mechanism of amyloidogenesis elevated by a nanoplastic trigger, shedding a new light on the neurological burden of plastic pollution.

Despite offering significant conveniences, plastic materials contribute substantially in developing environmental hazards and pollutants. Plastic trash that has not been adequately managed may eventually break down into fragments caused by human or ecological factors. Arguably, the crucial element for determining the biological toxicities of plastics are micro/nano-forms of plastics (MPs/NPs), which infiltrate the mammalian tissue through different media and routes. Infiltration of MPs/NPs across the intestinal barrier leads to microbial architectural dysfunction, which further modulates the population of gastrointestinal microbes. Thereby, it triggers inflammatory mediators (e.g., IL-1α/β, TNF-α, and IFN-γ) by activating specific receptors located in the gut barrier. Mounting evidence indicates that MPs/NPs disrupt host pathophysiological function through modification of junctional proteins and effector cells. Moreover, the alteration of microbial diversity by MPs/NPs causes the breakdown of the blood-brain barrier and translocation of metabolites (e.g., SCFAs, LPS) through the vagus nerve. Potent penetration affects the neuronal networks, neuronal protein accumulation, acceleration of oxidative stress, and alteration of neurofibrillary tangles, and hinders distinctive communicating pathways. Conclusively, alterations of these neurotoxic factors are possibly responsible for the associated neurodegenerative disorders due to the exposure of MPs/NPs. In this review, the hypothesis on MPs/NPs associated with gut microbial dysbiosis has been interlinked to the distinct neurological impairment through the gut-brain axis.

The neurological implications of micro- and nanoplastic exposure have recently come under scrutiny due to the environmental prevalence of these synthetic materials. Parkinson's disease (PD) is a major neurological disorder clinically characterized by intracellular Lewy-body inclusions and dopaminergic neuronal death. These pathological hallmarks of PD, according to Braak's hypothesis, are mediated by the afferent propagation of α synuclein (αS) via the enteric nervous system, or the so-called gut-brain axis. Here we first examined the effect of enteric exposure to polystyrene nanoplastics on the peripheral and central pathogenesis of A53T, a representative αS mutant. Specifically, the polystyrene nanoplastics accelerated the amyloid aggregation of A53T αS, which subsequently elevated the in vitro production of glial activation biomarkers, cytokines, and reactive oxygen species and compromised mitochondrial and lysosomal membrane integrity, further shifting cellular metabolite profiles in association with PD pathophysiology. In vivo, coadministration of the polystyrene nanoplastics and A53T αS facilitated their synergistic gut-to-brain transmission in mice, leading to progressive impairment of physical and motor skills in resemblance to characteristic PD symptoms. This study provides insights into the response and vulnerability of Parkinson's gut-brain axis to polystyrene nanoplastics.

Micro- and nano-plastics (MNPs) are ubiquitously distributed in the environment, infiltrate organisms through multiple pathways, and accumulate, thus posing potential threats to human health. MNP exposure elicits changes in microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), thereby precipitating immune, neurological, and other toxic effects. The investigation of MNP exposure and its effect on miRNA expression has garnered increasing attention. Following MNP exposure, circRNAs serve as miRNA sponges by modulating gene expression, while lncRNAs function as competing endogenous RNAs (ceRNAs) by fine-tuning target gene expression and consequently impacting protein translation and physiological processes in cells. Dysregulated miRNA expression mediates mitochondrial dysfunction, inflammation, and oxidative stress, thereby increasing the risk of neurodegenerative diseases, cardiovascular diseases, and cancer. This tract, blood, urine, feces, placenta, and review delves into the biotoxicity arising from dysregulated miRNA expression due to MNP exposure and addresses the challenges encountered in this field. This study provides novel insights into the connections between MNPs and disease risk.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the dysfunction and progressive death of cerebral and spinal motor neurons. Preliminary epidemiological research has hinted at a relationship between environmental risks and the escalation of ALS, but the underlying reasons remain mostly mysterious. Here we show that nanosize polystyrene plastics (PS) induce ALS-like symptoms and illustrate the related molecular mechanism. When exposed to PS, cells endure internal oxidative stress, which leads to the aggregation of TAR DNA-binding protein 43 kDa (TDP-43), triggering ALS-like characteristics. In addition, the oxidized heat shock protein 70 fails to escort TDP-43 back to the nucleus. The cytoplasmic accumulation of TDP-43 facilitates the formation of a complex between PS and TDP-43, enhancing the condensation and solidification of TDP-43. These findings are corroborated through in silico and in vivo assays. Altogether, our work illustrates a unique toxicological mechanism induced by nanoparticles and provides insights into the connection between environmental pollution and neurodegenerative disorders.

In the realm of Alzheimer's disease, the most prevalent form of dementia, the impact of environmental factors has ignited intense curiosity due to its substantial burden on global health. Recent investigations have unveiled these environmental factors as key contributors, shedding new light on their profound influence. Notably, emerging evidence highlights the detrimental role of various environmental contaminants in the incidence and progression of Alzheimer's disease. These contaminants encompass a broad spectrum, including air pollutants laden with ozone, neurotoxic metals like lead, aluminum, manganese, and cadmium, pesticides with their insidious effects, and the ubiquitous presence of plastics and microplastics. By meticulously delving into the intricate web connecting environmental pollutants and this devastating neurological disorder, this comprehensive chapter takes a deep dive into their involvement as significant risk factors for Alzheimer's disease. Furthermore, it explores the underlying molecular mechanisms through which these contaminants exert their influence, aiming to unravel the complex interactions that drive the pathogenesis of the disease. Additionally, this chapter proposes potential strategies to mitigate the detrimental effects of these environmental contaminants on brain health, with the ultimate goal of restoring and preserving typical cognitive function. Through this comprehensive exploration, we aim to enhance our understanding of the multifaceted relationship between neurotoxins and Alzheimer's disease, providing a solid foundation for developing innovative models and advancing our knowledge of the intricate pathological processes underlying this debilitating condition.

Pollution of micro/nano-plastics (MPs/NPs) is ubiquitously prevalent in the environment, leading to an unavoidable exposure of the human body. Despite the protection of the blood-brain barrier, MPs/NPs can be transferred and accumulated in the brain, which subsequently exert negative effects on the brain. Nevertheless, the potential neurodevelopmental and/or neurodegenerative risks of MPs/NPs remain largely unexplored. In this review, we provide a systematic overview of recent studies related to the neurotoxicity of MPs/NPs. It covers the environmental hazards and human exposure pathways, translocation and distribution into the brain, the neurotoxic effects, and the possible mechanisms of environmental MPs/NPs. MPs/NPs are widely found in different environment matrices, including air, water, soil, and human food. Ambient MPs/NPs can enter the human body by ingestion, inhalation and dermal contact, then be transferred into the brain via the blood circulation and nerve pathways. When MPs/NPs are present in the brain, they can initiate a series of molecular or cellular reactions that may harm the blood-brain barrier, cause oxidative stress, trigger inflammatory responses, affect acetylcholinesterase activity, lead to mitochondrial dysfunction, and impair autophagy. This can result in abnormal protein folding, loss of neurons, disruptions in neurotransmitters, and unusual behaviours, ultimately contributing to the initiation and progression of neurodegenerative changes and neurodevelopmental abnormalities. Key challenges and further research directions are also proposed in this review as more studies are needed to focus on the potential neurotoxicity of MPs/NPs under realistic conditions.

Mitochondrial dysfunction and metal ion imbalance are recognized as pathological hallmarks of Alzheimer's Disease (AD), leading to deposition of β-amyloid (Aβ) thereby and inducing neurotoxicity, activating apoptosis, eliciting oxidative stress, and ultimately leading to cognitive impairment. In this study, the red blood cell membrane (RBC) was used as a vehicle for encapsulating carbon quantum dots (CQD) and polydopamine (PDA), creating a nanocomposite (PDA-CQD/RBC). This nanocomposite was combined with near-infrared light (NIR) for AD treatment. The RBC offers anti-immunorecognition properties to evade immune clearance, PDA exhibits enzyme-mimicking activity to mitigate oxidative stress damage, and CQD acts as a chelating agent for metal ions (Cu), effectively preventing Cu-mediated aggregation of Aβ. Furthermore, the local heating induced by near-infrared laser irradiation can dismantle the formed Aβ fibers and enhance the blood-brain barrier's permeability. Both in vitro and animal experiments have shown that PDA-CQD/RBC, in combination with NIR, mitigates neuroinflammation, and ameliorates behavioral deficits in mice. This approach targets multiple pathological pathways, surpassing the limitations of single-target treatments and enhancing therapeutic efficacy while decelerating disease progression.

Autophagy is markedly impaired in Alzheimer's disease (AD). Here we reveal unique autophagy dysregulation within neurons in five AD mouse models in vivo and identify its basis using a neuron-specific transgenic mRFP-eGFP-LC3 probe of autophagy and pH, multiplex confocal imaging and correlative light electron microscopy. Autolysosome acidification declines in neurons well before extracellular amyloid deposition, associated with markedly lowered vATPase activity and build-up of Aβ/APP-βCTF selectively within enlarged de-acidified autolysosomes. In more compromised yet still intact neurons, profuse Aβ-positive autophagic vacuoles (AVs) pack into large membrane blebs forming flower-like perikaryal rosettes. This unique pattern, termed PANTHOS (poisonous anthos (flower)), is also present in AD brains. Additional AVs coalesce into peri-nuclear networks of membrane tubules where fibrillar β-amyloid accumulates intraluminally. Lysosomal membrane permeabilization, cathepsin release and lysosomal cell death ensue, accompanied by microglial invasion. Quantitative analyses confirm that individual neurons exhibiting PANTHOS are the principal source of senile plaques in amyloid precursor protein AD models.

Micro- and nanoplastics have become a significant concern, due to their ubiquitous presence in the environment. These particles can be internalized by the human body through ingestion, inhalation, or dermal contact, and then they can interact with environmental or biological molecules, such as proteins, resulting in the formation of the protein corona. However, information on the role of protein corona in the human body is still missing. Coarse-grain models of the nanoplastics and pentapeptides were created and simulated at the microscale to study the role of protein corona. Additionally, a lipid bilayer coarse-grain model was reproduced to investigate the behavior of the coronated nanoplastics in proximity of a lipid bilayer. Hydrophobic and aromatic amino acids have a high tendency to create stable bonds with all nanoplastics. Moreover, polystyrene and polypropylene establish bonds with polar and charged amino acids. When the coronated nanoplastics are close to a lipid bilayer, different behaviors can be observed. Polyethylene creates a single polymeric chain, while polypropylene tends to break down into its single chains. Polystyrene can both separate into its individual chains and remain aggregated. The protein corona plays an important role when interacting with the nanoplastics and the lipid membrane. More studies are needed to validate the results and to enhance the complexity of the systems.

The potential toxicity of nanoplastics on plants has previously been illustrated, but whether nanoplastics could cause neurotoxicity, especially to higher animals, remains unclear. We now demonstrate that nanoplastics can be deposited in the brain via nasal inhalation, triggering neuron toxicity and altering the animal behavior. Polystyrene nanoparticles (PS-NPs) of PS-COOH and PS-NH are used as models for nanoplastics. We designed a microfluidic chip to evaluate the PS-NPs with different concentrations, surface ligands, and sizes to interact with neurons. Smaller PS-NPs can induce more cellular uptake than larger PS-NPs. PS-NPs with a size of 80 nm can reach and deposit in the brain of mice via aerosol inhalation. Mice inhaling PS-NPs exhibit fewer activities in comparison to those inhaling water droplets. An obvious neurotoxicity of the nanoplastics could be observed from the results of the inhibition of AChE activities. Our results show the potential significance of the physiochemical properties of organic nanoplastics on depositing in mammalian brains by nasal inhalation.

As nanotheranostics, Congo red/Rutin-MNPs combine the abilities of diagnosis and treatment of Alzheimer's disease (AD). The biocompatible nanotheranostics system based on iron oxide magnetic nanoparticles, with ultrasmall size and excellent magnetic properties, can specifically detect amyloid plaques by magnetic resonance imaging, realize targeted delivery of AD therapeutic agents, achieve drug controlled release by H2O2 response, and prevent oxidative stress.

Fibrillogenesis of amyloid β-protein (Aβ) is pathologically associated with Alzheimer's disease (AD), so modulating Aβ aggregation is crucial for AD prevention and treatment. Herein, a zwitterionic polymer with short dimethyl side chains (pID) is synthesized and conjugated with a heptapeptide inhibitor (Ac-LVFFARK-NH, LK7) to construct zwitterionic polymer-inhibitor conjugates for enhanced inhibition of Aβ aggregation. However, it is unexpectedly found that the LK7@pID conjugates remarkably promote Aβ fibrillization to form more fibrils than the free Aβ system but effectively eliminate Aβ-induced cytotoxicity. Such an unusual behavior of the LK7@pID conjugates is unraveled by extensive mechanistic studies. First, the hydrophobic environment within the assembled micelles of LK7@pID promotes the hydrophobic interaction between Aβ molecules and LK7@pID, which triggers Aβ aggregation at the very beginning, making fibrillization occur at an earlier stage. Second, in the aggregation process, the LK7@pID micelles disassemble by the intensive interactions with Aβ, and LK7@pID participates in the fibrillization by being embedded in the Aβ fibrils, leading to the formation of hybrid and heterogeneous fibrillar aggregates with a different structure than normal Aβ fibrils. This unique Trojan horse-like feature of LK7@pID conjugates has not been observed for any other inhibitors reported previously and may shed light on the design of new modulators against β-amyloid cytotoxicity.

As environmental plastic waste degrades, it creates an abundance of diverse microplastic particles. Consequently, microplastics contaminate drinking water and many staple food products, meaning the oral ingestion of microplastics is an important exposure route for the human population. Microplastics have long been considered inert, however their ability to promote microbial dysbiosis as well as gut inflammation and dysfunction suggests they are more noxious than first thought. More alarmingly, there is evidence for microplastics permeating from the gut throughout the body, with adverse effects on the immune and nervous systems. Coupled with the now-accepted role of the gut-brain axis in neurodegeneration, these findings support the hypothesis that this ubiquitous environmental pollutant is contributing to the rising incidence of neurodegenerative diseases, like Alzheimer's disease and Parkinson's disease. This comprehensive narrative review explores the consequences of oral microplastic exposure on the gut-brain-axis by considering current evidence for gastrointestinal uptake and disruption, immune activation, translocation throughout the body, and neurological effects. As microplastics are now a permanent feature of the global environment, understanding their effects on the gut, brain, and whole body will facilitate critical further research and inform policy changes aimed at reducing any adverse consequences.

The mean global lifetime risk of neurological disorders such as stroke, Alzheimer's disease (AD), and Parkinson's disease (PD) has shown a large effect on economy and society. Researchers are still struggling to find effective drugs to treat neurological disorders and drug delivery through the blood-brain barrier (BBB) is a major challenge to be overcome. The BBB is a specialized multicellular barrier between peripheral blood circulation and neural tissue. Unique and selective features of the BBB allow it to tightly control brain homeostasis as well as the movement of ions and molecules. Failure in maintaining any of these substances causes BBB breakdown and subsequently enhances neuroinflammation and neurodegeneration. BBB disruption is evident in many neurological conditions. Nevertheless, the majority of currently available therapies have tremendous problems with drug delivery into the impaired brain. Nanoparticle (NP)-mediated drug delivery has been considered a profound substitute to solve this problem. NPs are colloidal systems with a size range of 1-1000 nm which can encapsulate therapeutic payloads, improve drug passage across the BBB, and target specific brain areas in neurodegenerative/ischemic diseases. A wide variety of NPs has been displayed for the efficient brain delivery of therapeutics via intravenous administration, especially when their surfaces are coated with targeting moieties. Here, we discuss recent advances in the development of NP-based therapeutics for the treatment of stroke, PD, and AD, as well as the factors affecting their efficacy after systemic administration.

The interest in nanoparticles (NPs) and their effects on living organisms has been continuously growing in the last decades. A special interest is focused on the effects of NPs on the central nervous system (CNS), which seems to be the most vulnerable to their adverse effects. Non-metallic NPs seem to be less toxic than metallic ones; thus, the application of non-metallic NPs in medicine and industry is growing very fast. Hence, a closer look at the impact of non-metallic NPs on neural tissue is necessary, especially in the context of the increasing prevalence of neurodegenerative diseases. In this review, we summarize the current knowledge of the in vitro and in vivo neurotoxicity of non-metallic NPs, as well as the mechanisms associated with negative or positive effects of non-metallic NPs on the CNS.