Liquid-liquid phase separation in Alzheimer's disease

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Pathological aggregation of tau and amyloid-beta proteins are central to Alzheimer's disease (AD).
• The precise pathological mechanisms driving AD remain incompletely understood.
• Liquid-liquid phase separation (LLPS) is emerging as a critical regulator in cellular processes and diseases, particularly neurodegeneration.

Purpose of the Study:

• To review the current understanding of liquid-liquid phase separation (LLPS) in the context of Alzheimer's disease (AD).
• To summarize the influence of various factors on tau protein LLPS and aggregation.
• To discuss the role of LLPS in amyloid-beta aggregation and cross-interactions between AD-related proteins.

Main Methods:

• Literature review synthesizing recent findings on LLPS in AD.
• Focus on the impact of metal ions, small-molecule inhibitors, and protein partners on tau LLPS.
• Examination of LLPS in amyloid-beta aggregation and inter-protein interactions.

Main Results:

• LLPS significantly influences the aggregation and toxic oligomerization of tau protein.
• LLPS plays a crucial role in the aggregation process of amyloid-beta.
• Cross-interactions between amyloidogenic proteins are modulated by LLPS.

Conclusions:

• LLPS is a key mechanism underlying the pathological protein aggregation in Alzheimer's disease.
• Understanding LLPS provides novel insights into AD pathogenesis.
• This review highlights fundamental methods for studying LLPS in the context of AD.