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

Abstract

Summary 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.

13C-isotope-editing of nanoscale infrared images reveals the action of an inhibi­tory peptide against amyloid-β aggregation

“…A second finding is that NCAM1-PrP promotes the aggregation of the protein S100A9 by destabilizing the native structure and creating a misfolded state. 54 It has therefore been suggested that NCAM1-PrP unfolds or dissolves structured proteins by interaction with amyloidogenic sequences, 39 which is in line with our proposal that NCAM1-PrP is able to destabilize Aβ fibrils. for the mixed sample; E: optical phase at 1587 cm −1 ; F: optical phase at 1587 cm −1 minus optical phase at 1629 cm −1 overlayed with a height image.…”

“…Our interpretation is in line with previous findings. NCAM1-PrP was found to inhibit secondary nucleation of Aβ in a similar way as BRICHOS, 39 which is known to coat fibrils and thus prevents the surface-catalyzed formation of new fibrils. 55 The analogous action of NCAM1-PrP thus suggests that it can bind to Aβ fibrils and the mixed composition of the fibrils in our Aβ:NCAM1-PrP images supports this view.…”

“…Our results for the interaction of Aβ with the inhibitory peptide NCAM1-PrP indicate that the latter is able to dissolve pre-formed Aβ fibrils, which is in line with its known anti-amyloid activity. 38,39 Supplementary Files This is a list of supplementary les associated with this preprint. Click to download.…”

“…The aggregation of Aβ and of the human prion protein can be inhibited by certain cell-penetrating peptides (CPPs) in vitro, [37][38][39][40] which target secondary nucleation 39 and counteract the lethal damage inflicted by the Aβ peptide on neuroblastoma cells. 38 These particular CPPs contain a signal sequence for secretion and a short sequence from an amyloidogenic polypeptide: either from the prion protein or from Aβ.…”

Amyloid-like RIP1/RIP3 RHIM Fragments’ Characterization and Application as a Drug Depot

“…From the stock solutions, 20 μM, 100 μM, or 1 mM concentrations of peptides were prepared by dissolving in 100 mM Ammonium Acetate, pH 7. Ammonium acetate was widely used as a buffer for amyloid peptides’ aggregation [ 39 , 40 ]. Hence, we have chosen ammonium acetate as the buffer for our studies.…”