The link between amyloid β and ferroptosis pathway in Alzheimer's disease progression.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY
Naďa Majerníková, Alejandro Marmolejo-Garza, Casandra Salinas Salinas, Minh D A Luu, Yuequ Zhang, Marina Trombetta-Lima, Tamara Tomin, Ruth Birner-Gruenberger, Šárka Lehtonen, Jari Koistinaho, Justina C Wolters, Scott Ayton, Wilfred F A den Dunnen, Amalia M Dolga
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Abstract

Alzheimer's disease (AD) affects millions of people worldwide and represents the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Here we evaluate if Aβ is associated with ferroptosis pathways in post-mortem human brain tissue and whether ferroptosis inhibition could attenuate Aβ-related effects in human brain organoids. Performing positive pixel density scoring on immunohistochemically stained post-mortem Brodmann Area 17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 and glutathione peroxidase 4 in the grey matter. Differentiating between white and grey matter, allowed for a more precise understanding of the disease's impact on different brain regions. In addition, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids at day 50 of differentiation. Differential gene expression analysis of RNAseq of AD organoids compared to isogenic controls indicated activation of the ferroptotic pathway. This was also supported by results from untargeted proteomic analysis revealing significant changes between AD and isogenic brain organoids. Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.

阿尔茨海默病进展过程中淀粉样蛋白 β 与铁蛋白沉积途径之间的联系
阿尔茨海默病(AD)影响着全球数百万人,是最常见的痴呆症。淀粉样β(Aβ)斑块和神经纤维缠结(NFTs)是阿尔茨海默病的两大特征,旨在干扰它们形成的治疗策略效果一般或没有效果。最近的证据表明,铁变态反应(一种由铁积累和脂质过氧化引起的程序性细胞死亡)是导致注意力缺失症发病的原因之一。现有的铁变态反应与 AD 之间的联系主要基于细胞培养和动物研究,而来自人类脑组织的证据却很有限。在此,我们评估了 Aβ 是否与死后人脑组织中的铁蛋白沉积途径有关,以及抑制铁蛋白沉积是否能减弱人脑器官组织中 Aβ 的相关效应。对免疫组化染色的死后布罗德曼17区切片进行阳性像素密度评分发现,伴随着AD病理学的发展,灰质中的核受体共激活因子4和谷胱甘肽过氧化物酶4的表达减少。区分白质和灰质有助于更准确地了解这种疾病对不同脑区的影响。此外,在人AD iPSCs衍生的脑皮质器官组织分化第50天时,抑制铁氧化酶可防止Aβ病理变化、减少脂质过氧化并恢复铁储存。与同源对照组相比,AD 有机体的 RNAseq 差异基因表达分析表明铁凋亡途径被激活。非靶向蛋白质组分析的结果也证明了这一点,该分析揭示了AD与同源脑有机体之间的显著变化。确定Aβ斑块的发展与参与铁凋亡的分子通路失调之间的因果关系对于开发潜在的治疗干预措施至关重要。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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