Implications of liquid-liquid phase separation and ferroptosis in Alzheimer's disease

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.