Targeting Liquid-Liquid Phase Separation and Autophagy in Alzheimer's Disease: Insights into Molecular Mechanisms and Therapeutic Potential.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, marked by cognitive decline and memory loss. Its multifactorial etiology involves genetic, environmental, and cellular factors, with key pathological features including amyloid-beta (Aβ) plaques and tau tangles. Recent studies have highlighted the roles of liquid-liquid phase separation (LLPS) and autophagy in AD onset and progression. LLPS, an emerging biophysical phenomenon, facilitates protein aggregation and may contribute to early disease stages. Dysregulated autophagy results in the accumulation of toxic proteins, such as Aβ and tau, exacerbating neurodegeneration. This review explores the interplay between LLPS and autophagy in AD, a relationship often overlooked in the literature. It examines their biological mechanisms, synergistic effects on AD pathology, and potential therapeutic strategies. Additionally, we discuss the therapeutic potential of both natural and non-natural compounds in modulating LLPS and autophagy. While compounds like curcumin show promise, a comprehensive framework for their targeted use remains under development. This review provides theoretical support for the advancement of more precise AD therapies.