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Dietary lipophilic iron alters amyloidogenesis and microglial morphology in Alzheimer's disease knock-in APP mice
Metallomics ( IF 3.4 ) Pub Date : 2018-02-02 00:00:00 , DOI: 10.1039/c8mt00004b
Douglas G. Peters 1, 2, 3, 4, 5 , Alexis N. Pollack 1, 2, 3, 4 , Keith C. Cheng 2, 3, 4, 6 , Dongxiao Sun 2, 3, 4, 7 , Takaomi Saido 8, 9, 10, 11 , Michael P. Haaf 4, 12, 13, 14 , Qing X. Yang 2, 3, 4, 15 , James R. Connor 1, 2, 3, 4 , Mark D. Meadowcroft 1, 2, 3, 4, 15
Affiliation  

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 APPNL-F and APPNL-G-F 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.

中文翻译:

饮食中的亲脂性铁改变阿尔茨海默氏病敲入APP小鼠的淀粉样蛋白生成和小胶质细胞形态

阿尔茨海默氏病(AD)是一种进行性神经退行性疾病,其病理特征是淀粉样β(Aβ)沉积,小胶质细胞增生和铁动态异常。据信由于体内稳态失调而引起的不稳定铁的增加促进了淀粉样蛋白的生成。游离铁在Aβ斑块形成过程中掺入聚集的淀粉样肽中,并增加了斑块周围氧化应激的可能性。这项工作的目的是观察脑铁水平在时间上如何影响Aβ斑块形成,斑块铁浓度和小胶质细胞增生。我们喂食了人性化的APP NL-F和APP NL-GF敲打小鼠亲脂性铁化合物3,5,5-三甲基己酰基二茂铁(TMHF)和缺铁饮食十二个月。相对于对照饮食,TMHF使脑铁升高22%,而铁缺乏使脑铁降低21%。用TMHF增加脑铁可加速斑块形成,增加Aβ染色并增加淀粉样斑块的老年形态。脑铁增加与斑块铁负荷和小胶质铁夹杂物增加有关。TMHF减少了IBA1 +小胶质细胞的分支长度,同时增加了指示小胶质细胞活化的圆度。这项工作表明,用TMHF增强小鼠脑铁可增强铁样整合到Aβ斑块和相关的小胶质细胞增生中,使人的阿尔茨海默氏病表型更加人性化。
更新日期:2018-02-02
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