Understanding ApoE4 Aggregation in Late-Onset Alzheimer’s Disease

Introduction

Alzheimer's disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. One of the key pathological features of AD is the accumulation of amyloid-beta (Aβ) peptides in the brain, which leads to the formation of plaques. Apolipoprotein E (ApoE), a protein involved in lipid metabolism, plays a crucial role in the aggregation of Aβ peptides. In particular, the ApoE4 isoform is strongly associated with increased risk and earlier onset of AD. In this blog post, we will discuss a recent research article that sheds light on the molecular mechanism behind ApoE4 aggregation in late-onset AD.

The Structure and Aggregation Tendencies of ApoE4

The study, published in the Journal of Molecular Neurodegeneration, used a combination of X-ray crystallography, mass spectrometry, and molecular dynamics simulations to investigate the structure and aggregation tendencies of ApoE4. The researchers found that ApoE4 forms V-shaped dimeric structures, which have a higher propensity to aggregate compared to the non-pathological ApoE3 structure. The V-shaped dimeric structure is stabilized by salt bridges between positively charged residues in the N-terminal domain and negatively charged residues in the C-terminal domain. The researchers also identified a key mutation in ApoE4, C112R, which destabilizes the salt bridges and increases the aggregation propensity.

Implications for Developing Targeted Drugs and Corrector Molecules

Understanding the molecular basis of ApoE4 aggregation is crucial for developing targeted drugs and corrector molecules to combat the devastating effects of neurodegenerative diseases. The study's findings suggest that stabilizing the salt bridges in ApoE4 could be a potential strategy for preventing its aggregation and reducing the risk of AD. Furthermore, the study identified a small molecule inhibitor that disrupts the V-shaped dimeric structure of ApoE4 and reduces its aggregation propensity. This inhibitor could serve as a starting point for developing effective drugs to treat AD.

Conclusion

The study's findings offer valuable insights into the structure and aggregation tendencies of ApoE4, a protein strongly associated with increased risk and earlier onset of AD. The researchers identified a key mutation, C112R, which destabilizes the salt bridges in ApoE4 and increases its aggregation propensity. Understanding the molecular basis of ApoE4 aggregation is crucial for developing targeted drugs and corrector molecules to combat the devastating effects of neurodegenerative diseases. The study's findings open up new avenues for potential treatment strategies and offer hope in the fight against AD.

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Journal Article: Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer's Disease drug candidate (link)