Iron Dyshomeostasis Induces Binding of APP to BACE1 for Amyloid Pathology, and Impairs APP/Fpn1 Complex in Microglia: Implication in Pathogenesis of Cerebral Microbleeds
Iron Dyshomeostasis Induces Binding of APP to BACE1 for Amyloid Pathology, and Impairs APP/Fpn1 Complex in Microglia: Implication in Pathogenesis of Cerebral Microbleeds
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铁稳态失调诱导 APP 与 BACE1 结合以形成淀粉样蛋白病理学，并损害小胶质细胞中的 APP/Fpn1 复合物：对脑微出血发病机制的影响
DOI：
10.1177/0963689719831707
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发表时间：
2019-08-01
影响因子：
3.3
通讯作者：
Liu, Xueyuan
中科院分区：
文献类型：
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作者：
Gong, Li;Tian, Xiangzhu;Liu, Xueyuan
脑微出血（CMB）作为脑小血管病的一个公认标志物，与血管性认知功能障碍有关。铁积累和淀粉样蛋白前体（APP）失调被认为是CMB进展的病理标志，但它们的相互作用尚不清楚。在这项研究中，我们发现随着FeCl 3处理的增加，淀粉样蛋白形成显著增加，并且在300 μ M FeCl 3浓度下观察到APP代谢和铁稳态蛋白（铁蛋白，Fpn 1，铁调节蛋白）表达的明显变化。进一步的结果表明，细胞外铁积累可能会诱导APP与BACE 1结合形成淀粉样蛋白，并降低APP/Fpn 1介导铁输出的能力。我们的研究结果反映了铁稳态异常和淀粉样蛋白病理之间的可能关系，可能有助于阐明血管性认知障碍中CMB的潜在发病机制。
As a putative marker of cerebral small vessel disease, cerebral microbleeds (CMBs) have been associated with vascular cognitive impairment. Both iron accumulation and amyloid protein precursor (APP) dysregulation are recognized as pathological hallmarks underlying the progression of CMBs, but their cross-talk is not yet understood. In this study, we found a profound increase of amyloid formation with increasing FeCl3 treatment, and a distinct change in APP metabolism and expression of iron homeostasis proteins (ferritin, Fpn1, iron regulatory protein) was observed at the 300 uM concentration of FeCl3. Further results revealed that extracellular iron accumulation might potentially induce binding of APP to BACE1 for amyloid formation and decrease the capability of APP/Fpn1 in mediating iron export. Our findings in this study, reflecting a probable relationship between iron dyshomeostasis and amyloid pathology, may help shed light on the underlying pathogenesis of CMBs in vascular cognitive impairment.