Atomistic Insights into Structural Differences between E3 and E4 Isoforms of Apolipoprotein E.

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Apolipoprotein E (ApoE) isoforms play critical roles in lipid metabolism and neurological health.
• Apolipoprotein E4 (ApoE4) is the strongest genetic risk factor for Alzheimer's disease (AD), while Apolipoprotein E3 (ApoE3) is neutral.
• The structural and functional divergence between ApoE4 and ApoE3, stemming from a single amino acid difference, remains poorly understood due to the lack of an ApoE4 3D structure.

Purpose of the Study:

• To computationally model the 3D atomistic structure of Apolipoprotein E4 (ApoE4).
• To elucidate the key structural differences between monomeric ApoE4 and ApoE3.
• To understand how these structural differences contribute to the differential risk of Alzheimer's disease.

Main Methods:

• Microsecond-long atomistic simulations were employed to model the 3D structure of ApoE4.
• Comparative analysis of the simulated structures of ApoE4 and ApoE3 was performed.
• Identification of partially folded intermediates and assessment of thermodynamic stability and structural rigidity.

Main Results:

• The study successfully generated a plausible 3D atomistic structure of ApoE4.
• ApoE4 exhibits significantly lower thermodynamic stability, reduced structure, and less topological rigidity compared to ApoE3.
• Simulations identified multiple partially folded intermediates for ApoE4, consistent with its reported molten globule state and higher aggregation propensity.

Conclusions:

• The single amino acid difference between ApoE4 and ApoE3 leads to distinct structural properties.
• ApoE4's inherent instability and altered structure contribute to its increased aggregation propensity, a key factor in Alzheimer's disease pathogenesis.
• This structural insight provides a mechanistic link between ApoE genotype and Alzheimer's disease risk.