Alzheimer's disease (AD) is a public health crisis due to debilitating cognitive symptoms and lack of curative treatments, in the context of increasing prevalence. Thus, it is critical to identify modifiable risk factors. High levels of meat consumption may increase AD risk. Many toxins are formed during meat cooking such as heterocyclic aromatic amines (HAAs). Our prior studies have shown that HAAs produce dopaminergic neurotoxicity. Given the mechanistic and pathological overlap between AD and dopaminergic disorders we investigated whether exposure to 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP), a prevalent dietary HAA formed during high-temperature meat cooking, may produce AD-relevant neurotoxicity. Here, C57BL/6 mice were treated with 100 or 200 mg/kg PhIP for 8 h or 75 mg/kg for 4 weeks and 16 weeks. PhIP exposure for 8 h produced oxidative damage, and AD-relevant alterations in hippocampal synaptic proteins, Amyloid-beta precursor protein (APP), and β-Site amyloid precursor protein cleaving enzyme 1 (BACE1). PhIP exposure for 4 weeks resulted in an increase in BACE1. PhIP exposure for 16 weeks resulted in increased hippocampal oxidative damage, APP, BACE1, Aβ aggregation, and tau phosphorylation. Quantification of intracellular nitrotyrosine revealed oxidative damage in cholinergic neurons after 8 h, 4 weeks and 16 weeks of PhIP exposure. Our study demonstrates that increase in oxidative damage, APP and BACE1 might be a possible mechanism by which PhIP promotes Aβ aggregation. Given many patients with AD or PD exhibit neuropathological overlap, our study suggests that HAA exposure should be further studied for roles in mediating pathogenic overlap.

中文翻译：

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啮齿动物体内的PhIP暴露会产生与阿尔茨海默氏病潜在相关的神经病理学。

阿尔茨海默氏病（AD）是一种公共健康危机，原因是在日益流行的情况下，使人的认知症状恶化并且缺乏治疗方法。因此，确定可修改的风险因素至关重要。大量食用肉类可能会增加AD风险。在肉类烹饪过程中会形成许多毒素，例如杂环芳香胺（HAAs）。我们先前的研究表明，HAA会产生多巴胺能神经毒性。考虑到AD与多巴胺能障碍之间的机理和病理学重叠，我们研究了是否暴露于2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）（一种在高温肉食过程中形成的常见饮食HAA） ，可能产生与AD相关的神经毒性。在此，以100或200 mg / kg PhIP处理C57BL / 6小鼠8小时，或以75 mg / kg PhIP处理4周和16周。PhIP暴露8 h会产生氧化损伤，并在海马突触蛋白，淀粉样β前体蛋白（APP）和β-位淀粉样前体蛋白裂解酶1（BACE1）中发生与AD相关的改变。PhIP暴露4周导致BACE1增加。PhIP暴露16周导致海马氧化损伤，APP，BACE1，Aβ聚集和tau磷酸化增加。PhIP暴露8小时，4周和16周后，细胞内硝基酪氨酸的定量显示胆碱能神经元的氧化损伤。我们的研究表明，氧化损伤，APP和BACE1的增加可能是PhIP促进Aβ聚集的可能机制。鉴于许多AD或PD患者表现出神经病理学重叠，