Systematic and standardized comparison of reported amyloid-β receptors for sufficiency, affinity, and Alzheimer's disease relevance

J Biol Chem. 2019 Apr 12;294(15):6042-6053. doi: 10.1074/jbc.RA118.006252. Epub 2019 Feb 20.


Oligomeric assemblies of amyloid-β (Aβ) peptide (Aβo) in the brains of individuals with Alzheimer's disease (AD) are toxic to neuronal synapses. More than a dozen Aβ receptor candidates have been suggested to be responsible for various aspects of the molecular pathology and memory impairment in mouse models of AD. A lack of consistent experimental design among previous studies of different receptor candidates limits evaluation of the relative roles of these candidates, producing some controversy within the field. Here, using cell-based assays with several Aβ species, including Aβo from AD brains obtained by autopsy, we directly compared the Aβ-binding capacity of multiple receptor candidates while accounting for variation in expression and confirming cell surface expression. In a survey of 15 reported Aβ receptors, only cellular prion protein (PrPC), Nogo receptor 1 (NgR1), and leukocyte immunoglobulin-like receptor subfamily B member 2 (LilrB2) exhibited direct binding to synaptotoxic assemblies of synthetic Aβ. Both PrPC and NgR1 preferentially bound synaptotoxic oligomers rather than nontoxic monomers, and the method of oligomer preparation did not significantly alter our binding results. Hippocampal neurons lacking both NgR1 and LilrB2 exhibited a partial reduction of Aβo binding, but this reduction was lower than in neurons lacking PrPC under the same conditions. Finally, binding studies with soluble Aβo from human AD brains revealed a strong affinity for PrPC, weak affinity for NgR1, and no detectable affinity for LilrB2. These findings clarify the relative contributions of previously reported Aβ receptors under controlled conditions and highlight the prominence of PrPC as an Aβ-binding site.

Keywords: Alzheimer disease; Aβ receptor; EphA1; EphA4; EphB2; FZD5; FcγRIIb; NLGN1; NR1; NR2B; PGRMC1; RAGE; SorLA; amyloid-β (Aβ); leukocyte immunoglobulin-like receptor subfamily B member 2 (LilrB2), Nogo receptor 1 (NgR1); mGluR5; nAchRa7; neurodegeneration; oligomer; p75NTR; prion; prion protein (PrPC); receptor; sortilin.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Disease Models, Animal
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Knockout
  • Neurons / metabolism
  • Neurons / pathology
  • Nogo Receptor 1 / genetics
  • Nogo Receptor 1 / metabolism*
  • PrPC Proteins / genetics
  • PrPC Proteins / metabolism*
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*


  • Amyloid beta-Peptides
  • LILRB2 protein, human
  • Membrane Glycoproteins
  • Nogo Receptor 1
  • PrPC Proteins
  • RTN4R protein, human
  • Receptors, Immunologic
  • Rtn4r protein, mouse