| First Author | Huang TY | Year | 2017 |
| Journal | J Exp Med | Volume | 214 |
| Issue | 12 | Pages | 3669-3685 |
| PubMed ID | 29114064 | Mgi Jnum | J:251935 |
| Mgi Id | MGI:6106449 | Doi | 10.1084/jem.20171413 |
| Citation | Huang TY, et al. (2017) SORLA attenuates EphA4 signaling and amyloid beta-induced neurodegeneration. J Exp Med 214(12):3669-3685 |
| abstractText | 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 beta (Abeta) precursor protein to decrease levels of proteotoxic Abeta oligomers, whether SORLA can counteract synaptic dysfunction induced by Abeta 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 Abeta 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 Abeta-induced neurodegeneration in AD. |
