Department of Neurosurgery, The Pennsylvania State University - College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033, USA and Department of Neural and Behavioral Science, The Pennsylvania State University - College of Medicine, Hershey, Pennsylvania, USA.
Department of Neurosurgery, The Pennsylvania State University - College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033, USA.
Metallomics. 2018 Mar 1;10(3):426-443. doi: 10.1039/c8mt00004b. Epub 2018 Feb 9.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized pathologically by amyloid beta (Aβ) deposition, microgliosis, and iron dyshomeostasis. Increased labile iron due to homeostatic dysregulation is believed to facilitate amyloidogenesis. Free iron is incorporated into aggregating amyloid peptides during Aβ plaque formation and increases potential for oxidative stress surrounding plaques. The goal of this work was to observe how brain iron levels temporally influence Aβ plaque formation, plaque iron concentration, and microgliosis. We fed humanized APP and APP knock-in mice lipophilic iron compound 3,5,5-trimethylhexanoyl ferrocene (TMHF) and iron deficient diets for twelve months. TMHF elevated brain iron by 22% and iron deficiency decreased brain iron 21% relative to control diet. Increasing brain iron with TMHF accelerated plaque formation, increased Aβ staining, and increased senile morphology of amyloid plaques. Increased brain iron was associated with increased plaque-iron loading and microglial iron inclusions. TMHF decreased IBA1+ microglia branch length while increasing roundness indicative of microglial activation. This body of work suggests that increasing mouse brain iron with TMHF potentiates a more human-like Alzheimer's disease phenotype with iron integration into Aβ plaques and associated microgliosis.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其病理特征为淀粉样蛋白β（Aβ）沉积、小胶质细胞激活和铁动态失衡。由于稳态失调导致的不稳定铁增加被认为有助于淀粉样蛋白的形成。在 Aβ斑块形成过程中，游离铁被整合到聚集的淀粉样肽中，增加了斑块周围发生氧化应激的潜力。这项工作的目的是观察脑铁水平如何随时间影响 Aβ斑块形成、斑块铁浓度和小胶质细胞激活。我们用亲脂性铁化合物 3,5,5-三甲基己酰基二茂铁（TMHF）和缺铁饮食喂养人源化 APP 和 APP 基因敲入小鼠 12 个月。TMHF 使脑铁增加了 22%，而缺铁使脑铁减少了 21%，与对照饮食相比。用 TMHF 增加脑铁加速了斑块形成，增加了 Aβ染色，并增加了淀粉样斑块的老年形态。脑铁的增加与斑块铁负荷和小胶质细胞铁内含物的增加有关。TMHF 减少了 IBA1+小胶质细胞的分支长度，同时增加了圆形度，表明小胶质细胞激活。这项工作表明，用 TMHF 增加小鼠脑铁会增强更类似于人类的阿尔茨海默病表型，铁整合到 Aβ斑块中，并与小胶质细胞激活相关。
