Systematic and standardized comparison of reported amyloid-ß receptors for sufficiency, affinity, and Alzheimer's disease relevance.
J Biol Chem
; 294(15): 6042-6053, 2019 04 12.
Article
em En
| MEDLINE
| ID: mdl-30787106
ABSTRACT
Oligomeric assemblies of amyloid-ß (Aß) peptide (Aßo) in the brains of individuals with Alzheimer's disease (AD) are toxic to neuronal synapses. More than a dozen Aß 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 Aß species, including Aßo from AD brains obtained by autopsy, we directly compared the Aß-binding capacity of multiple receptor candidates while accounting for variation in expression and confirming cell surface expression. In a survey of 15 reported Aß 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 Aß. 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 Aßo binding, but this reduction was lower than in neurons lacking PrPC under the same conditions. Finally, binding studies with soluble Aßo 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 Aß receptors under controlled conditions and highlight the prominence of PrPC as an Aß-binding site.
Palavras-chave
Alzheimer disease; Aß receptor; EphA1; EphA4; EphB2; FZD5; FcγRIIb; NLGN1; NR1; NR2B; PGRMC1; RAGE; SorLA; amyloid-ß (Aß); leukocyte immunoglobulin-like receptor subfamily B member 2 (LilrB2), Nogo receptor 1 (NgR1); mGluR5; nAchRa7; neurodegeneration; oligomer; p75NTR; prion; prion protein (PrPC); receptor; sortilin
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Glicoproteínas de Membrana
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Receptores Imunológicos
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Peptídeos beta-Amiloides
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Proteínas PrPC
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Doença de Alzheimer
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Receptor Nogo 1
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article