Ahmed Giasuddin, Rahaman Md Shiblur, Perez Enrique, Khan Khalid M
Department of Biology and Chemistry, Texas A&M International University, Laredo, TX 78041, USA.
Department of Public Health, College of Health Sciences, Sam Houston State University, Huntsville, TX 77341, USA.
J Xenobiot. 2025 Mar 24;15(2):47. doi: 10.3390/jox15020047.
Numerous epidemiological studies indicate that populations exposed to environmental toxicants such as heavy metals have a higher likelihood of developing Alzheimer's disease (AD) compared to those unexposed, indicating a potential association between heavy metals exposure and AD. The aim of this review is to summarize contemporary mechanistic research exploring the associations of four important metals, arsenic (As), manganese (Mn), lead (Pb), and cadmium (Cd), with AD and possible pathways, processes, and molecular mechanisms on the basis of data from the most recent mechanistic studies. Primary research publications published during the last decade were identified via a search of the PubMed Database. A thorough literature search and final screening yielded 45 original research articles for this review. Of the 45 research articles, 6 pertain to As, 9 to Mn, 21 to Pb, and 9 to Cd exposures and AD pathobiology. Environmental exposure to these heavy metals induces a wide range of pathological processes that intersect with well-known mechanisms leading to AD, such as oxidative stress, mitochondrial dysfunction, protein aggregation, neuroinflammation, autophagy dysfunction, and tau hyperphosphorylation. While exposure to single metals shares some affected pathways, certain effects are unique to specific metals. For instance, Pb disrupts the blood-brain barrier (BBB) and mitochondrial functions and alters AD-related genes epigenetically. Cd triggers neuronal senescence via p53/p21/Rb. As disrupts nitric oxide (NO) signaling, cortical, and synaptic function. Mn causes glutamate excitotoxicity and dopamine neuron damage. Our review provides a deeper understanding of biological mechanisms showing how metals contribute to AD. Information regarding the potential metal-induced toxicity relevant to AD may help us develop effective therapeutic AD intervention, treatment, and prevention.
大量流行病学研究表明，与未接触环境毒物（如重金属）的人群相比，接触这些毒物的人群患阿尔茨海默病（AD）的可能性更高，这表明重金属暴露与AD之间可能存在关联。本综述的目的是基于最新机制研究的数据，总结当代机制研究，探讨四种重要金属，即砷（As）、锰（Mn）、铅（Pb）和镉（Cd）与AD的关联以及可能的途径、过程和分子机制。通过搜索PubMed数据库确定了过去十年发表的主要研究出版物。经过全面的文献搜索和最终筛选，得到了45篇用于本综述的原创研究文章。在这45篇研究文章中，6篇与As有关，9篇与Mn有关，21篇与Pb有关，9篇与Cd暴露及AD病理生物学有关。环境暴露于这些重金属会引发广泛的病理过程，这些过程与导致AD的知名机制相互交叉，如氧化应激、线粒体功能障碍、蛋白质聚集、神经炎症、自噬功能障碍和tau蛋白过度磷酸化。虽然接触单一金属会有一些共同的受影响途径，但某些影响是特定金属所特有的。例如，Pb会破坏血脑屏障（BBB）和线粒体功能，并在表观遗传上改变与AD相关的基因。Cd通过p53/p21/Rb触发神经元衰老。As会破坏一氧化氮（NO）信号传导、皮层和突触功能。Mn会导致谷氨酸兴奋性毒性和多巴胺神经元损伤。我们的综述更深入地了解了金属如何导致AD的生物学机制。有关与AD相关的潜在金属诱导毒性的信息可能有助于我们开发有效的AD治疗干预、治疗和预防方法。
