Second Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, China.
Department of Anatomy, Basic Medical College, Qiqihar Medical University, Qiqihar, China.
Dement Geriatr Cogn Disord. 2024;53(3):107-118. doi: 10.1159/000537883. Epub 2024 Apr 4.
The objective of the study was to explore the molecular mechanism of long noncoding RNA (lncRNA) LINC00472 in Alzheimer's disease (AD) and identify potential novel targets for AD therapy.
Ferroptosis-related lncRNAs were screened by GEO database. AD mouse model was constructed for in vivo experiments. The content of Aβ protein and tau protein hyperphosphorylation were examined in hippocampal tissue samples of mice. Subsequently, HT22 cells were induced with Aβ25-35 to establish a neuronal injury model of AD in vitro. The expression of FOXO1, a key gene for ferroptosis, was verified by overexpressing/knocking down the LINC00472. The effects of LINC00472 on ROS and lipid peroxidation content, GPX4, and tau protein in AD model cells were examined by ROS assay, MDA assay, Western blot, and qRT-PCR. Subsequently, the expression of iron ion, FTH, TfRC, and Fpn protein were detected in AD cells.
The level of FOXO1 was positively correlated with the degree of AD. In vivo experiments showed that the expression of Aβ and tau hyperphosphorylated were significantly reduced in the inhibitor group and iron was significantly reduced relative to the AD group. In the AD cell model, the content of lipid peroxide was upregulated, GPX4 protein and mRNA were decreased, and phosphorylation of tau protein was enhanced in the AD cell model relative to the control group. Whereas knocking down LINC00472 inhibited the upregulation of lipid peroxide, decreased the level of GPX4, and enhanced tau protein phosphorylation, and reduced iron accumulation in AD cells.
LINC00472 affects ferroptosis in AD by regulating iron accumulation in neuronal cells.
本研究旨在探索长链非编码 RNA（lncRNA）LINC00472 在阿尔茨海默病（AD）中的分子机制，并寻找 AD 治疗的潜在新靶点。
通过 GEO 数据库筛选铁死亡相关 lncRNA。构建 AD 小鼠模型进行体内实验。检测小鼠海马组织样本中 Aβ 蛋白和 tau 蛋白过度磷酸化的含量。随后，用 Aβ25-35 诱导 HT22 细胞，建立 AD 神经元损伤模型。通过过表达/敲低 LINC00472 验证铁死亡关键基因 FOXO1 的表达。通过 ROS 测定、MDA 测定、Western blot 和 qRT-PCR 检测 AD 模型细胞中 LINC00472 对 ROS 和脂质过氧化含量、GPX4 和 tau 蛋白的影响。随后，检测 AD 细胞中铁离子、FTH、TfRC 和 Fpn 蛋白的表达。
FOXO1 的表达水平与 AD 的严重程度呈正相关。体内实验表明，抑制剂组的 Aβ 和 tau 过度磷酸化表达明显低于 AD 组，铁离子含量明显低于 AD 组。在 AD 细胞模型中，与对照组相比，脂质过氧化产物含量升高，GPX4 蛋白和 mRNA 减少，tau 蛋白磷酸化增强。而敲低 LINC00472 抑制了脂质过氧化产物的上调，降低了 GPX4 水平，并增强了 tau 蛋白磷酸化，减少了 AD 细胞中铁的积累。
LINC00472 通过调节神经元细胞中铁的积累影响 AD 中的铁死亡。
