神经细胞的死亡是阿尔茨海默病(AD)发展过程中普遍存在的现象。然而,触发神经元细胞死亡的机制尚不清楚。其潜在机制包括可溶性淀粉样蛋白β(Aβ)聚集形成不溶性淀粉样蛋白斑块,tau蛋白的异常磷酸化和细胞内神经原纤维缠结(NFTs)的形成,神经炎症,铁性凋亡,氧化应激,液-液相分离(LLPS)和金属离子紊乱。其中,铁凋亡是铁依赖性脂质过氧化驱动的细胞死亡,新的证据表明铁凋亡参与AD的病理过程。对铁死亡的敏感性与许多生物过程紧密相关。此外,新出现的证据表明,LLPS对调节人类健康和疾病有很大的影响,尤其是AD。可溶性Aβ可以经历LLPS形成液体状液滴,这可能导致不溶性淀粉样蛋白斑块的形成。同时,tau通过LLPS机制具有很高的冷凝倾向,这可能导致NFT的形成。在这次审查中,我们总结了有关LLPS和铁凋亡在AD中的最新进展。我们的主要重点是阐述Aβ的影响,tau蛋白,铁离子,和脂质氧化对AD病理学域内铁死亡和LLPS的复杂机制的影响。此外,我们深入研究了在AD背景下LLPS和铁凋亡之间发生的复杂的交叉相互作用。我们的研究结果有望为AD的临床研究和靶向治疗提供理论和实验基础。
Neuronal cell demise represents a prevalent occurrence throughout the advancement of Alzheimer\'s disease (AD). However, the mechanism of triggering the death of neuronal cells remains unclear. Its potential mechanisms include aggregation of soluble amyloid-beta (Aβ) to form insoluble amyloid plaques, abnormal phosphorylation of tau protein and formation of intracellular neurofibrillary tangles (NFTs), neuroinflammation, ferroptosis, oxidative stress, liquid-liquid phase separation (LLPS) and metal ion disorders. Among them, ferroptosis is an iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. The sensitivity to ferroptosis is tightly linked to numerous biological processes. Moreover, emerging evidences indicate that LLPS has great impacts on regulating human health and diseases, especially AD. Soluble Aβ can undergo LLPS to form liquid-like droplets, which can lead to the formation of insoluble amyloid plaques. Meanwhile, tau has a high propensity to condensate via the mechanism of LLPS, which can lead to the formation of NFTs. In this review, we summarize the most recent advancements pertaining to LLPS and ferroptosis in AD. Our primary focus is on expounding the influence of Aβ, tau protein, iron ions, and lipid oxidation on the intricate mechanisms underlying ferroptosis and LLPS within the domain of AD pathology. Additionally, we delve into the intricate cross-interactions that occur between LLPS and ferroptosis in the context of AD. Our findings are expected to serve as a theoretical and experimental foundation for clinical research and targeted therapy for AD.