Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers

Abstract

Oligomeric forms of amyloid-β (Aβ) peptide are known to be the primary neurotoxic species in Alzheimer's disease (AD), but how they interact with neurons to produce their deleterious effects is unclear. Over ten different cell-surface receptors for Aβ have been described, but their molecular interactions with Aβ assemblies and their relative contributions to mediating AD pathology have remained uncertain. In the present work, we have used super-resolution microscopy to directly visualize Aβ-receptor interactions at the nanometer scale. We report that one documented Aβ receptor, the cellular prion protein, PrP C , specifically inhibits the polymerization Aβ fibrils via a unique mechanism in which it binds specifically to the rapidly growing end of each fibril, thereby blocking polarized elongation at that end. PrP C binds neurotoxic oligomers and protofibrils in a similar fashion, suggesting that it may recognize a common, end-specific, structural motif on all of these assemblies. Finally, two other candidate Aβ receptors, FcγRIIb and LilrB2, affect Aβ fibril growth in a manner similar to PrP C . Taken together, our results suggest that neurotoxic signaling by several different receptors may be activated by common molecular interactions with both fibrillar and oligomeric Aβ ligands. Targeting such interactions with small molecules represents an attractive therapeutic strategy for treatment of AD.

Structural details of amyloid beta oligomers in complex with human prion protein as revealed by solid-state MAS NMR spectroscopy

“…We also investigated the homogeneity and structural characteristics of Aβoligo using two samples containing uniformly 13 C, 15 N labeled Aβoligo in complex with non-labeled huPrP in different molar ratios ( Table 1).…”

“…The purification of recombinant full-length huPrP(23-230) and C-terminally truncated huPrP(23-144) either unlabeled or uniformly 13 C, 15 N labeled was performed as described previously 33 .…”

“…For site-specific assignment 15 N-13 C correlation spectra were recorded using SPECIFIC-CP 52 for frequency selective polarization transfer from 15 N to either 13 Cα or 13 CO and subsequent DARR-mixing. 2D NCA, NCACX and 3D NCACX and NCOCX spectra were used for the sequential walk through the backbone.…”

“…PrP C is a high-affinity cell-surface receptor for Aoligo 12,13 as well as for fibrillar A [14][15][16] . It has been suggested that binding of Aβoligo to membrane-anchored PrP C mediates Aβ toxicity during AD by mediating synapse damage 17 and the blockade of long-term potentiation by Aβoligo 12,18 via activation of Fyn-kinase pathways 19,20 , but this has also been questioned [21][22][23][24] .…”

“…In all these in vitro preparations A oligomers and early stage protofibrils are stabilized and prevented from elongation by PrP, which has been shown to preferentially bind to fast growing fibril and oligomer ends 15 .…”