Environmental aluminum oxide inducing neurodegeneration in human neurovascular unit with immunity.

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.

Human mini-brains for reconstituting central nervous system disorders.

Neurological disorders in the central nervous system (CNS) are progressive and irreversible diseases leading to devastating impacts on patients' life as they cause cognitive impairment, dementia, and even loss of essential body functions. The development of effective medicines curing CNS disorders is, however, one of the most ambitious challenges due to the extremely complex functions and structures of the human brain. In this regard, there are unmet needs to develop simplified but physiopathologically-relevant brain models. Recent advances in the microfluidic techniques allow multicellular culture forming miniaturized 3D human brains by aligning parts of brain regions with specific cells serving suitable functions. In this review, we overview designs and strategies of microfluidics-based human mini-brains for reconstituting CNS disorders, particularly Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI), vascular dementia (VD), and environmental risk factor-driven dementia (ERFD). Afterward, the applications of the mini-brains in the area of medical science are introduced in terms of the clarification of pathogenic mechanisms and identification of promising biomarkers. We also present expanded model systems ranging from the CNS to CNS-connecting organ axes to study the entry pathways of pathological risk factors into the brain. Lastly, the advantages and potential challenges of current model systems are addressed with future perspectives.