Molecular and structural insight into the differences among common and rare Alzheimer's disease-associated apoE variants.

Abstract

Alzheimer's Disease (AD) is the leading cause of dementia worldwide with multiple risk modifying factors identified through GWAS including common apoE variants (apoE2, apoE3, apoE4). Additionally, rare apoE variants including apoE3-R136S (Christchurch), apoE3-V236E (Jacksonville), and apoE4-R251G may alter AD risk. ApoE interacts with AD-associated proteins TREM2 and amyloid-beta (Aβ), holding interactions at the hinge and LDL receptor binding domain (LDLRBD) for TREM2 and the N-terminal helices and lipid binding domain (LBD) for Aβ. The structure, conformation, and dynamics differences among these apoE variants that may alter apoE interactions with TREM2 and Aβ are unknown. In this study, we investigated how these apoE isoforms differ in secondary structure, conformation, and dynamics using molecular dynamics (MD) simulations. The apoE variants’ structures were obtained by mutating the known NMR structure of lipid-free apoE3 (PDBID: 2L7B). We performed 500 ns MD simulations for the six apoE variants with the last 250 ns of equilibrated trajectories used for analysis. The apoE variants differed primarily in the conformational stability of the N-terminal, hinge, and LBD regions. Further, apoE variants differed in secondary structure, and specifically in the length, occupancy, and type of helices that make up the N-terminal, hinge, and LBD regions. Our dynamic cross-correlated motion analysis revealed variations in the correlated motions between the hinge, LDLRBD, and LBD regions of apoE variants. The conformational stability, secondary structure, and dynamic motion differences among the apoE variants provide important insight into how these common and rare apoE variants may alter interactions with TREM2, Aβ, and other AD-associated proteins to affect the risk of developing AD. Acknowledgements: This work was supported by the NIH 1R01AG068395-01A1, NIH 5T32EB023872-04, and Alzheimer's Drug Discovery Foundation.