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| Item Type: | Article |
|---|---|
| Title: | SORLA attenuates EphA4 signaling and amyloid, β-induced neurodegeneration |
| Creators Name: | Huang, T.Y., Zhao, Y., Jiang, L.L., Li, X., Liu, Y., Sun, Y., Piña-Crespo, J.C., Zhu, B., Masliah, E., Willnow, T.E., Pasquale, E.B. and Xu, H. |
| 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 {beta} (A{beta}) precursor protein to decrease levels of proteotoxic A{beta} oligomers, whether SORLA can counteract synaptic dysfunction induced by A{beta} 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 A{beta} 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 A{beta}-induced neurodegeneration in AD. |
| Keywords: | Alzheimer Disease, Amyloid Beta-Protein Precursor, Ephrins, Growth Cones, HEK293 Cells, LDL-Receptor Related Proteins, Ligands, Long-Term Potentiation, Membrane Transport Proteins, Mutation, Nerve Degeneration, Protein Binding, Protein Domains, Receptor, EphA4, Receptors, LDL, Synapses, Animals, Mice, Inbred BALB C, Mice, Transgenic |
| Source: | Journal of Experimental Medicine |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Volume: | 214 |
| Number: | 12 |
| Page Range: | 3669-3685 |
| Date: | 4 December 2017 |
| Official Publication: | https://doi.org/10.1084/jem.20171413 |
| PubMed: | View item in PubMed |
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