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Impact of metal exposure on neurodegenerative diseases: advances in understanding neurotoxicological mechanisms
Liu Zhen, Zhou Jing, Yang Dan, Liu Wan, Zhao Yan, Luo Yujun, Cao Biwei
2026, 30 (12):
3109-3126.
doi: 10.12307/2026.735
BACKGROUND: Metal exposure has been closely linked to the onset and progression of neurodegenerative diseases.
OBJECTIVE: To systematically and comprehensively elucidate the impact of metal exposure on neurodegenerative diseases and summarize the neurotoxicological mechanisms underlying metal exposure-induced neurodegeneration.
METHODS: The first author conducted a computerized search of CNKI, Web of Science, and PubMed databases for literature published up to February 2025. The search terms were “Metal exposure, Manganese, Iron, Zinc, Copper, Cadmium, Lead, Aluminum, Neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease, Multiple sclerosis, Amyotrophic lateral sclerosis, Huntington’s disease” in Chinese and English. According to the inclusion criteria, a total of 204 articles were ultimately included for review and analysis.
RESULTS AND CONCLUSION: (1) Exposure to manganese systematically drives neurodegenerative processes via mitochondrial oxidative stress, neuroinflammatory responses, and protein homeostasis disruption. (2) Iron-induced abnormal free iron accumulation triggers mitochondrial dysfunction, proteostasis imbalance, neuroinflammation, and epigenetic dysregulation. The inflammatory microenvironment induced by neuroinflammation exacerbates iron accumulation, leading to neuronal apoptosis, Lewy body deposition, amyloid pathology, and blood-brain barrier disruption, thereby promoting neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. (3) Zinc overload damages neurons through dual pathways: intracellular zinc influx induces endoplasmic reticulum stress, causing calcium imbalance and mitochondrial dysfunction, while synaptic zinc activates the reactive oxygen species-glutamate toxicity axis. Both pathways amplify apoptotic signals via the p38MAPK/JNK pathway and synergize with Toll-like receptor 4/nuclear factor-κB-mediated neuroinflammation to drive neurodegenerative diseases, such as Alzheimer’s disease. (4) Copper exerts neurotoxicity via Fenton reaction-mediated oxidative stress, protein aggregation, cuproptosis, and neurotransmitter imbalance. Concurrently, blood-brain barrier disruption exacerbates copper accumulation, forming a self-reinforcing neurotoxic network that accelerates neurodegeneration. (5) Cadmium induces oxidative stress, mitochondrial dysfunction, apoptosis, calcium dysregulation, neurotransmitter disruption, neuroinflammation, and blood-brain barrier damage, collectively contributing to neurodegeneration. (6) Lead hijacks metal transporters to induce oxidative stress and mitochondrial apoptosis, upregulates ryanodine receptors to cause calcium overload and synaptic plasticity impairment, and exacerbates β-amyloid deposition and synaptic damage via epigenetic dysregulation, thereby driving neurodegeneration. (7) Aluminum disrupts iron metabolism to induce iron overload and ferroptosis, interferes with acetylcholine metabolism to impair cholinergic function, inhibits the insulin receptor substrate 1/phosphatidylinositol 3-kinase/protein kinase B pathway to promote tau hyperphosphorylation and β-amyloid deposition, and activates the c-Jun N-terminal kinase/NOD-like receptor protein 3 pathway to trigger necroptosis and pyroptosis. These mechanisms synergistically induce neuroinflammation, synaptic dysfunction, and neuronal apoptosis, ultimately leading to cognitive deficits and neurodegeneration. (8) Toxic ions released by metallic implants (e.g., excess zinc, iron) can trigger neuronal oxidative stress, excitotoxicity, and mitochondrial dysfunction, interfering with neural regeneration. Ion leaching can be mitigated by optimizing scaffold porosity, mechanical properties, and surface coating technologies (e.g., silver nanoparticles). (9) Metal chelators reduce neurotoxicity by binding free metal ions. They not only clear iron deposits and dissolve β-amyloid aggregates in Alzheimer’s disease but also synergize with stem cell transplantation to alleviate local oxidative stress and inflammation in traumatic brain injury, thereby enhancing neural repair efficacy. (10) Emerging tissue engineering strategies for countering metal toxicity include the development of targeted delivery systems (e.g., calcium ethylenediaminetetraacetate-loaded nanoparticles traversing the blood-brain barrier to eliminate heavy metals) and smart responsive materials (e.g., metal ion-sensitive hydrogels dynamically regulating ion release). These approaches aim to precisely maintain the balance of essential metal elements within the neural microenvironment.
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