Environmental exposures and the etiopathogenesis of Alzheimer's disease: The potential role of BACE1 as a critical neurotoxic target.
Environmental exposures and the etiopathogenesis of Alzheimer's disease: The potential role of BACE1 as a critical neurotoxic target.
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DOI：
10.1002/jbt.22694
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发表时间：
2021-04
影响因子：
3.6
通讯作者：
Cannon JR
中科院分区：
文献类型：
--
作者：
Syeda T;Cannon JR
阿尔茨海默氏病 (AD) 是一场重大的公共卫生危机，因为它具有破坏性的认知症状、缺乏治疗方法以及患病率不断上升。大多数病例在 65 岁之后呈散发性（>95% 的病例），这表明环境因素在疾病发病机制中发挥着重要作用。环境神经毒物与帕金森病和 AD 等神经退行性疾病有关。 AD 动物模型和体外研究揭示了潜在的神经病理学机制，但 AD 相关环境神经毒性的生化和分子基础仍然知之甚少。 β 位点淀粉样蛋白前体蛋白裂解酶 1 (BACE1) 是环境引起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，并且 BACE1 的表达和活性在 AD 大脑中增加。虽然有关 BACE1 响应环境损害的文献有限，但当前的研究以及广泛的 AD 神经生物学文献表明，BACE1 作为重要的神经毒性靶点值得关注。在此，我们批判性地回顾了调节 BACE1 的环境神经毒物（例如金属、农药、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）及其潜在作用机制的研究。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 会受到与 AD 病理相关的环境风险因素的改变，这意味着在 AD 管理和研究中应考虑 BACE1 抑制及其作为生物标志物的使用。
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. While 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. While 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.
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影响因子：
4.8
作者：
Bennett, BD;Denis, P;Vassar, R
通讯作者：
Vassar, R
影响因子：
4.8
作者：
Bennett, BD;Babu-Khan, S;Vassar, R
通讯作者：
Vassar, R
DOI：
10.1007/s00420-003-0491-0
发表时间：
2004-05-01
影响因子：
3
作者：
Bast-Pettersen, R;Ellingsen, DG;Thomassen, Y
通讯作者：
Thomassen, Y
影响因子：
--
作者：
Angeloni C;Zambonin L;Hrelia S
通讯作者：
Hrelia S
影响因子：
5.1
作者：
Ayyalasomayajula, Neelima;Bandaru, Madhuri;Challa, Suresh
通讯作者：
Challa, Suresh