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Apolipoprotein A-I Mimetic 4F Peptide Generates Amyloid Cytotoxins by Forming Hetero-oligomers with β-amyloid

By Bikash Ranjan Sahoo, Michael E. Bekier, Zichen Liu, Vojc Kocman, Andrea K. Stoddard, G M Anantharamaiah, James Nowick, Carol A. Fierke, Yanzhuang Wang, Ayyalusamy Ramamoorthy

Posted 04 Aug 2019
bioRxiv DOI: 10.1101/722983

Apolipoproteins are involved in pathological conditions of Alzheimer disease (AD), truncated apolipoprotein fragments and beta-amyloid (Abeta) peptides coexist as neurotoxic heteromers within the plaques. Therefore, it is important to investigate these complexes at the molecular level to better understand their properties and roles in the pathology of AD. Here, we present a mechanistic insight into such heteromerization using a structurally homologue apolipoprotein fragment of apoA-I (4F) complexed with Abeta(M1-42) and characterize their toxicity. The 4F peptide slows down the aggregation kinetics of Abeta(M1-42) by constraining its structural plasticity. NMR and CD experiments identified 4F-Abeta(M1-42) heteromers as being comprised of unstructured Abeta(M1-42) and helical 4F. A uniform 2-fold reduction in Abeta42 15N/1H NMR signal intensities with no observable chemical shift perturbation indicated the formation of a large complex, which was further confirmed by diffusion NMR experiments. Microsecond scale atomistic molecular dynamics simulations showed that 4F interaction with Abeta(M1-42) is electrostatically driven and induces unfolding of Abeta(M1-42). Neurotoxicity profiling of Abeta(M1-42) complexed with 4F confirms a significant reduction in cell-viability and neurite growth. The molecular architecture of heteromerization between 4F and Abeta(M1-42) discovered in this study provides evidence towards our understanding of the role of apolipoproteins or their truncated fragments in exacerbating AD pathology.

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