SORLA attenuates EphA4 signaling and amyloid β–induced neurodegeneration
| العنوان: | SORLA attenuates EphA4 signaling and amyloid β–induced neurodegeneration |
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| المؤلفون: | Thomas E. Willnow, Timothy Y. Huang, Eliezer Masliah, Yan Liu, Xiaoguang Li, Juan C. Piña-Crespo, Huaxi Xu, Yingjun Zhao, Bing Zhu, Elena B. Pasquale, Yu Sun, Lu-Lin Jiang |
| المصدر: | The Journal of Experimental Medicine |
| بيانات النشر: | Rockefeller University Press, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Genetically modified mouse, Amyloid, Growth Cones, Long-Term Potentiation, Immunology, SORL1, Mice, Transgenic, Ligands, Article, Receptor tyrosine kinase, Amyloid beta-Protein Precursor, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, Alzheimer Disease, medicine, Animals, Humans, Immunology and Allergy, Receptor, LDL-Receptor Related Proteins, Research Articles, Mice, Inbred BALB C, biology, Chemistry, Neurodegeneration, Receptor, EphA4, Membrane Transport Proteins, Long-term potentiation, medicine.disease, Cell biology, HEK293 Cells, 030104 developmental biology, Receptors, LDL, Mutation, Nerve Degeneration, Synapses, LDL receptor, biology.protein, Ephrins, 030217 neurology & neurosurgery, Protein Binding |
| الوصف: | Huang et al. show that the Alzheimer’s disease (AD) risk factor SORLA inhibits amyloid β–induced synaptotoxicity and cognitive impairment through interacting with and subsequently inactivating EphA4. These findings provide a novel mechanism by which the SORLA loss-of-function mutation significantly increases AD risk. 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 β (Aβ) precursor protein to decrease levels of proteotoxic Aβ oligomers, whether SORLA can counteract synaptic dysfunction induced by Aβ 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 Aβ 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 Aβ-induced neurodegeneration in AD. |
| تدمد: | 1540-9538 0022-1007 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::47cbbcea54f1d6c4d2a01e09608c3648Test https://doi.org/10.1084/jem.20171413Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....47cbbcea54f1d6c4d2a01e09608c3648 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15409538 00221007 |
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