Neuritic plaques are pathognomonic and terminal lesions of Alzheimer's Disease (AD). They embody AD pathogenesis because they harbor in one space critical pathologic features of the disease: amyloid deposits, neurofibrillary degeneration (NFD), neuroinflammation, iron accumulation. Neuritic plaques are thought to arise from the conversion of diffuse extracellular deposits of amyloid beta protein (Aβ), and it is believed that during conversion amyloid toxicity creates the dystrophic neurites of neuritic plaques, as well as neurofibrillary tangles (NFTs). However, recent evidence from human post-mortem studies suggests a much different mechanism of neuritic plaque formation where the first step in their creation is neuronal degeneration driven by iron overload and ferroptosis. Similarly, NFTs represent corpses of iron-laden neurons that develop independent of Aβ deposits. In this review, we will focus on the role of free redox-active iron in the development of typical AD pathology, as determined largely by evidence obtained in human temporal lobe during early, preclinical stages of AD. The findings have allowed construction of a scheme of AD pathogenesis where brain iron is center stage and is involved in every step of the sequence of events that produce characteristic AD pathology. We will discuss how the study of preclinical AD has produced a fresh and revised assessment of AD pathogenesis that may be important for reconsidering current therapeutic efforts and guiding future ones. Significance Statement This review offers a novel perspective on AD pathogenesis where elevated brain iron plays a central role and is involved throughout the development of lesions. We review arguments against the amyloid cascade theory and explain how recent findings in humans during early preclinical disease support iron-mediated cell death and endogenous iron containment mechanisms as critical components of neuritic plaque formation and the ensuing dementia.

中文翻译：

---

阿尔茨海默病中神经炎斑块的铁死亡和发病机制。


中性斑块是阿尔茨海默病 （AD） 的特征性和终末期病变。它们体现了 AD 的发病机制，因为它们在一个空间中隐藏了该疾病的关键病理特征：淀粉样蛋白沉积、神经原纤维变性 （NFD）、神经炎症、铁蓄积。中性斑块被认为是由淀粉样蛋白 β （Aβ） 的弥漫性细胞外沉积物的转化引起的，并且据信在转化过程中淀粉样蛋白毒性会产生神经炎斑块的营养不良性神经突，以及神经原纤维缠结 （NFT）。然而，来自人类尸检研究的最新证据表明，神经炎斑块形成的机制大不相同，其中它们产生的第一步是由铁过载和铁死亡驱动的神经元变性。同样，NFT 代表独立于 Aβ 沉积物发育的含铁神经元尸体。在这篇综述中，我们将重点关注游离氧化还原活性铁在典型 AD 病理发展中的作用，这主要取决于在 AD 的早期临床前阶段在人类颞叶中获得的证据。这些发现允许构建一个 AD 发病机制方案，其中脑铁是中心舞台，并参与产生特征性 AD 病理的事件序列的每一步。我们将讨论临床前 AD 的研究如何对 AD 发病机制进行新的和修订的评估，这对于重新考虑当前的治疗工作和指导未来的治疗工作可能很重要。意义声明 本综述为 AD 发病机制提供了新的视角，其中脑铁升高起着核心作用，并参与整个病变的发展过程。 我们回顾了反对淀粉样蛋白级联理论的论点，并解释了在早期临床前疾病期间人类的最新发现如何支持铁介导的细胞死亡和内源性铁遏制机制作为神经炎斑块形成和随之而来的痴呆的关键组成部分。