Alzheimer's disease (AD) is a major public health crisis due to devastating cognitive symptoms, a lack of curative treatments, and increasing prevalence. Most cases are sporadic (>95% of cases) after the age of 65 years, implicating an important role of environmental factors in disease pathogenesis. Environmental neurotoxicants have been implicated in neurodegenerative disorders including Parkinson's Disease and AD. Animal models of AD and in vitro studies have shed light on potential neuropathological mechanisms, yet the biochemical and molecular underpinnings of AD‐relevant environmental neurotoxicity remain poorly understood. Beta‐site amyloid precursor protein cleaving enzyme 1 (BACE1) is a potentially critical pathogenic target of environmentally induced neurotoxicity. BACE1 clearly has a critical role in AD pathophysiology: It is required for amyloid beta production and expression and activity of BACE1 are increased in the AD brain. Though the literature on BACE1 in response to environmental insults is limited, current studies, along with extensive AD neurobiology literature suggest that BACE1 deserves attention as an important neurotoxic target. Here, we critically review research on environmental neurotoxicants such as metals, pesticides, herbicides, fungicides, polyfluoroalkyl substances, heterocyclic aromatic amines, advanced glycation end products, and acrolein that modulate BACE1 and potential mechanisms of action. Though more research is needed to clearly understand whether BACE1 is a critical mediator of AD‐relevant neurotoxicity, available reports provide convincing evidence that BACE1 is altered by environmental risk factors associated with AD pathology, implying that BACE1 inhibition and its use as a biomarker should be considered in AD management and research.

中文翻译：

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环境暴露和阿尔茨海默病的发病机制：BACE1 作为关键神经毒性靶点的潜在作用

阿尔茨海默病 (AD) 是一场重大的公共卫生危机，原因是破坏性的认知症状、缺乏治愈性治疗方法以及患病率增加。大多数病例在 65 岁之后是散发的（>95% 的病例），这表明环境因素在疾病发病机制中的重要作用。环境神经毒物与包括帕金森病和 AD 在内的神经退行性疾病有关。AD的动物模型和体外研究揭示了潜在的神经病理学机制，但与AD相关的环境神经毒性的生化和分子基础仍然知之甚少。β-位点淀粉样前体蛋白裂解酶 1 (BACE1) 是环境诱导的神经毒性的潜在关键致病靶点。BACE1 显然在 AD 病理生理学中具有关键作用：它是β-淀粉样蛋白产生所必需的，BACE1 的表达和活性在 AD 脑中增加。虽然关于 BACE1 应对环境损害的文献有限，但目前的研究以及广泛的 AD 神经生物学文献表明，BACE1 作为一个重要的神经毒性靶标值得关注。在这里，我们批判性地回顾了对环境神经毒物的研究，例如金属、杀虫剂、除草剂、杀菌剂、多氟烷基物质、杂环芳香胺、高级糖基化终产物和丙烯醛，它们可以调节 BACE1 和潜在的作用机制。虽然需要更多的研究来清楚地了解 BACE1 是否是 AD 相关神经毒性的关键介质，但现有的报告提供了令人信服的证据表明 BACE1 会被与 AD 病理学相关的环境风险因素改变，