Ministry of Education Key Laboratory of Molecular and Cellular Biology, Laboratory of Molecular Iron Metabolism, College of Life Sciences, Hebei Normal University, No. 20 Nanerhuan Eastern Road, Shijiazhuang, 050024, Hebei Province, China.
Mol Neurobiol. 2022 Sep;59(9):5574-5590. doi: 10.1007/s12035-022-02929-w. Epub 2022 Jun 23.
Brain iron overload is positively correlated with the pathogenesis of Alzheimer's disease (AD). However, the role of iron in AD pathology is not completely understood. Furin is the first identified mammalian proprotein convertase that catalyzes the proteolytic maturation of large numbers of prohormones and proproteins. The correlation between altered furin expression and AD pathology has been suggested, but the underlying mechanism remains to be clarified. Here, we found that the expression of furin in the hippocampus of Alzheimer's model APP/PS1 mice was significantly reduced, and we demonstrated that the reduction of furin was directly caused by hippocampal iron overload using wild-type mice with intrahippocampal injection of iron. In cultured neuronal cells, this suppression effect was observed as transcriptional inhibition. Regarding the changes of furin-mediated activities caused by hippocampal iron overload, we found that the maturation of brain-derived neurotrophic factor (BDNF) was impeded and the expression levels of synaptogenesis-related proteins were downregulated, leading to cognitive decline. Furthermore, iron chelation or furin overexpression in the hippocampus of APP/PS1 mice increased furin expression, restored synapse plasticity, and ameliorated cognitive decline. Therefore, the inhibitory effect of hippocampal iron accumulation on furin transcription may be an important pathway involved in iron-mediated synapse damage and memory loss in AD. This study provides new insights into the molecular mechanisms of the toxic effects of iron in neurons and AD pathophysiology and renders furin as a potential target for treatment of iron overload-related neurodegenerative diseases.
脑铁过载与阿尔茨海默病（AD）的发病机制呈正相关。然而，铁在 AD 病理中的作用尚未完全阐明。弗林是第一个被鉴定的哺乳动物前蛋白转化酶，可催化大量前激素和前蛋白的蛋白水解成熟。已经提出了弗林表达改变与 AD 病理之间的相关性，但潜在的机制仍需阐明。在这里，我们发现阿尔茨海默病模型 APP/PS1 小鼠海马中的弗林表达显著降低，并且我们证明通过向野生型小鼠海马内注射铁，铁过载直接导致弗林的减少。在培养的神经元细胞中，这种抑制作用表现为转录抑制。关于海马铁过载引起的弗林介导的活性变化，我们发现脑源性神经营养因子（BDNF）的成熟受到阻碍，突触发生相关蛋白的表达水平下调，导致认知能力下降。此外，APP/PS1 小鼠海马中的铁螯合或弗林过表达增加了弗林的表达，恢复了突触可塑性，并改善了认知能力下降。因此，海马铁蓄积对弗林转录的抑制作用可能是铁介导的突触损伤和 AD 中记忆丧失的重要途径。本研究为铁在神经元和 AD 病理生理学中的毒性作用的分子机制提供了新的见解，并使弗林成为治疗与铁过载相关的神经退行性疾病的潜在靶点。
