SORLA attenuates EphA4 signaling and amyloid ß-induced neurodegeneration.
J Exp Med
; 214(12): 3669-3685, 2017 Dec 04.
Article
em En
| MEDLINE
| ID: mdl-29114064
ABSTRACT
Sortilin-related receptor with LDLR class A repeats (SORLA, SORL1, or LR11) is a genetic risk factor associated with Alzheimer's disease (AD). Although SORLA is known to regulate trafficking of the amyloid ß (Aß) precursor protein to decrease levels of proteotoxic Aß oligomers, whether SORLA can counteract synaptic dysfunction induced by Aß oligomers remains unclear. Here, we show that SORLA interacts with the EphA4 receptor tyrosine kinase and attenuates ephrinA1 ligand-induced EphA4 clustering and activation to limit downstream effects of EphA4 signaling in neurons. Consistent with these findings, SORLA transgenic mice, compared with WT mice, exhibit decreased EphA4 activation and redistribution to postsynaptic densities, with milder deficits in long-term potentiation and memory induced by Aß oligomers. Importantly, we detected elevated levels of active EphA4 in human AD brains, where EphA4 activation is inversely correlated with SORLA/EphA4 association. These results demonstrate a novel role for SORLA as a physiological and pathological EphA4 modulator, which attenuates synaptotoxic EphA4 activation and cognitive impairment associated with Aß-induced neurodegeneration in AD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Membrana Transportadoras
/
Receptores de LDL
/
Precursor de Proteína beta-Amiloide
/
Proteínas Relacionadas a Receptor de LDL
/
Receptor EphA4
/
Degeneração Neural
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Exp Med
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Canadá