The amyloid-inhibiting NCAM-PrP peptide targets Aβ peptide aggregation in membrane-mimetic environments

Sylwia Król; Nicklas Österlund; Faraz Vosough; Jüri Jarvet; Sebastian Wärmländer; Andreas Barth; Leopold L Ilag; Mazin Magzoub; Astrid Gräslund; Cecilia Mörman

doi:10.1016/j.isci.2021.102852

The amyloid-inhibiting NCAM-PrP peptide targets Aβ peptide aggregation in membrane-mimetic environments

iScience. 2021 Jul 10;24(8):102852. doi: 10.1016/j.isci.2021.102852. eCollection 2021 Aug 20.

Affiliations

¹ Department of Biochemistry and Biophysics, Stockholm University, Stockholm, 106 91, Sweden.
² Department of Materials and Environmental Chemistry, Stockholm University, Stockholm, 106 91, Sweden.
³ Biology Program, Division of Science, New York University Abu Dhabi, Box 129188, Abu Dhabi, United Arab Emirates.

Abstract

Substantial research efforts have gone into elucidating the role of protein misfolding and self-assembly in the onset and progression of Alzheimer's disease (AD). Aggregation of the Amyloid-β (Aβ) peptide into insoluble fibrils is closely associated with AD. Here, we use biophysical techniques to study a peptide-based approach to target Aβ amyloid aggregation. A peptide construct, NCAM-PrP, consists of a largely hydrophobic signal sequence linked to a positively charged hexapeptide. The NCAM-PrP peptide inhibits Aβ amyloid formation by forming aggregates which are unavailable for further amyloid aggregation. In a membrane-mimetic environment, Aβ and NCAM-PrP form specific heterooligomeric complexes, which are of lower aggregation states compared to Aβ homooligomers. The Aβ:NCAM-PrP interaction appears to take place on different aggregation states depending on the absence or presence of a membrane-mimicking environment. These insights can be useful for the development of potential future therapeutic strategies targeting Aβ at several aggregation states.

Keywords: biophysics; molecular neuroscience; structural biology.