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bioRxiv · 10.1101/822361

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

Amin, L.·Harris, D. A.
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Abstract

Oligomeric forms of amyloid-{beta} (A{beta}) peptide are known to be the primary neurotoxic species in Alzheimers disease (AD), but how they interact with neurons to produce their deleterious effects is unclear. Over ten different cell-surface receptors for A{beta} have been described, but their molecular interactions with A{beta} 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 A{beta}-receptor interactions at the nanometer scale. We report that one documented A{beta} receptor, the cellular prion protein, PrPC, specifically inhibits the polymerization A{beta} 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. PrPC 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 A{beta} receptors, Fc{gamma}RIIb and LilrB2, affect A{beta} fibril growth in a manner similar to PrPC. Taken together, our results suggest that neurotoxic signaling by several different receptors may be activated by common molecular interactions with both fibrillar and oligomeric A{beta} ligands. Targeting such interactions with small molecules represents an attractive therapeutic strategy for treatment of AD.

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Amin, L., Harris, D. A.. 2019-10-29. Aβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers. https://doi.org/10.1101/822361

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