SORLA attenuates EphA4 signaling and amyloid β–induced neurodegeneration

Autor: 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
Rok vydání: 2017
Předmět:
Zdroj: The Journal of Experimental Medicine
ISSN: 1540-9538
0022-1007
DOI: 10.1084/jem.20171413
Popis: 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.
Databáze: OpenAIRE