“…5 d). The results showed significant increases in the production of H 2 O 2 (7.2 μM) in AlNP-treated chronic model compared to controls, corresponding to the concentrations promoting tauopathy and exacerbating neurological disorders 15 , 33 , 34 . Figure 5 Neurodegeneration caused by AlNP-reactive astrocytes.…”
Section: Resultsmentioning
confidence: 95%
“…This study also confirmed that the BBB-penetrating AlNPs promoted reactive astrocytes while soluble factors from AlNP-treated BBB minorly affected them. We recently reported that the induction of reactive astrocytes in response to pathogens or insoluble deposits in the brain and further contributed to neurodegeneration 33 , 34 . In accordance with these studies, we discovered that astrocytes retained the reactive phenotype expressing the high level of GFAP in response to AlNP treatment (Fig.…”
Aluminum oxide nanoparticle (AlNP), a ubiquitous neurotoxin highly enriched in air pollution, is often produced as an inevitable byproduct in the manufacturing of industrial products such as cosmetics and metal materials. Meanwhile, ALNP has emerged as a significant public health concern due to its potential association with neurological diseases. However, the studies about the neurotoxic effects of AlNP are limited, partially due to the lack of physiologically relevant human neurovascular unit with innate immunity (hNVUI). Here, we employed our AlNP-treated hNVUI model to investigate the underlying mechanism of AlNP-driven neurodegeneration. First, we validated the penetration of AlNP across a blood–brain barrier (BBB) compartment and found AlNP-derived endothelial cellular senescence through the p16 and p53/p21 pathways. Our study showed that BBB-penetrating AlNP promoted reactive astrocytes, which produced a significant level of reactive oxygen species (ROS). The astrocytic neurotoxic factors caused neuronal damage, including the synaptic impairment, the accumulation of phosphoric-tau proteins, and even neuronal death. Our study suggests that AlNP could be a potential environmental risk factor of neurological disorders mediated by neuroinflammation.
“…5 d). The results showed significant increases in the production of H 2 O 2 (7.2 μM) in AlNP-treated chronic model compared to controls, corresponding to the concentrations promoting tauopathy and exacerbating neurological disorders 15 , 33 , 34 . Figure 5 Neurodegeneration caused by AlNP-reactive astrocytes.…”
Section: Resultsmentioning
confidence: 95%
“…This study also confirmed that the BBB-penetrating AlNPs promoted reactive astrocytes while soluble factors from AlNP-treated BBB minorly affected them. We recently reported that the induction of reactive astrocytes in response to pathogens or insoluble deposits in the brain and further contributed to neurodegeneration 33 , 34 . In accordance with these studies, we discovered that astrocytes retained the reactive phenotype expressing the high level of GFAP in response to AlNP treatment (Fig.…”
Aluminum oxide nanoparticle (AlNP), a ubiquitous neurotoxin highly enriched in air pollution, is often produced as an inevitable byproduct in the manufacturing of industrial products such as cosmetics and metal materials. Meanwhile, ALNP has emerged as a significant public health concern due to its potential association with neurological diseases. However, the studies about the neurotoxic effects of AlNP are limited, partially due to the lack of physiologically relevant human neurovascular unit with innate immunity (hNVUI). Here, we employed our AlNP-treated hNVUI model to investigate the underlying mechanism of AlNP-driven neurodegeneration. First, we validated the penetration of AlNP across a blood–brain barrier (BBB) compartment and found AlNP-derived endothelial cellular senescence through the p16 and p53/p21 pathways. Our study showed that BBB-penetrating AlNP promoted reactive astrocytes, which produced a significant level of reactive oxygen species (ROS). The astrocytic neurotoxic factors caused neuronal damage, including the synaptic impairment, the accumulation of phosphoric-tau proteins, and even neuronal death. Our study suggests that AlNP could be a potential environmental risk factor of neurological disorders mediated by neuroinflammation.
“…We next explored the intoxication effects of toxins on astrocytes, as the astrocytes are the major glial cells gaining reactivity through their communication with neurons that are involved in eliminating damaged synapses. [ 29 , 30 , 31 , 32 , 33 ] To this end, we employed single‐cultured astrocytes as well as co‐cultured models of neurons and astrocytes, exposed to 1 n m BoNT/A (S2). Afterward, we performed immunostaining of glial fibrillary acidic protein (GFAP) to estimate the level of astrocyte reactivity (Figure 2g,h ).…”
Section: Resultsmentioning
confidence: 99%
“…In this study, we performed an investigative assay of BoNT/A by using an engineered 3D human tri‐culture system with human neural progenitor cells in a microfluidic platform. [ 28 , 29 ] The 3D construct was formed utilizing human NPC [ 30 , 31 ] differentiating into neurons and astrocytes in the center chamber of the microfluidic device. BoNT/A was added to the system after 3 weeks of differentiation in the central chamber.…”
Botulinum neurotoxin serotype A (BoNT/A) is widely used in therapeutics and cosmetics. The effects of multi‐dosed BoNT/A treatment are well documented on the peripheral nervous system (PNS), but much less is known on the central nervous system (CNS). Here, the mechanism of multi‐dosed BoNT/A leading to CNS neurodegeneration is explored by using the 3D human neuron‐glia model. BoNT/A treatment reduces acetylcholine, triggers astrocytic transforming growth factor beta, and upregulates C1q, C3, and C5 expression, inducing microglial proinflammation. The disintegration of the neuronal microtubules is escorted by microglial nitric oxide, interleukin 1β, tumor necrosis factor α, and interleukin 8. The microglial proinflammation eventually causes synaptic impairment, phosphorylated tau (pTau) aggregation, and the loss of the BoNT/A‐treated neurons. Taking a more holistic approach, the model will allow to assess therapeutics for the CNS neurodegeneration under the prolonged use of BoNT/A.
“…This device was used to develop models of CNS disorders, bacterial infections, cancer, or edema, by introducing Aβ (adding cells expressing APP variants), bacterial conditioned media or bacterial toxin, cancer cells, or ammonium chloride, respectively. The device allowed for both real-time and end-point analysis [ 224 ]. Microfluidic platforms have also been used to understand the neuroinflammatory processes in AD.…”
Section: In Vitro and Preclinical Studies For Alzheimer’s And Parkins...mentioning
Parkinson’s disease (PD) and Alzheimer’s disease (AD) are neurodegenerative disorders caused by the interaction of genetic, environmental, and familial factors. These diseases have distinct pathologies and symptoms that are linked to specific cell populations in the brain. Notably, the immune system has been implicated in both diseases, with a particular focus on the dysfunction of microglia, the brain’s resident immune cells, contributing to neuronal loss and exacerbating symptoms. Researchers use models of the neuroimmune system to gain a deeper understanding of the physiological and biological aspects of these neurodegenerative diseases and how they progress. Several in vitro and in vivo models, including 2D cultures and animal models, have been utilized. Recently, advancements have been made in optimizing these existing models and developing 3D models and organ-on-a-chip systems, holding tremendous promise in accurately mimicking the intricate intracellular environment. As a result, these models represent a crucial breakthrough in the transformation of current treatments for PD and AD by offering potential for conducting long-term disease-based modeling for therapeutic testing, reducing reliance on animal models, and significantly improving cell viability compared to conventional 2D models. The application of 3D and organ-on-a-chip models in neurodegenerative disease research marks a prosperous step forward, providing a more realistic representation of the complex interactions within the neuroimmune system. Ultimately, these refined models of the neuroimmune system aim to aid in the quest to combat and mitigate the impact of debilitating neuroimmune diseases on patients and their families.
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