Format

Send to

Choose Destination
J Exp Med. 2017 Dec 4;214(12):3669-3685. doi: 10.1084/jem.20171413. Epub 2017 Nov 7.

SORLA attenuates EphA4 signaling and amyloid β-induced neurodegeneration.

Author information

1
Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA.
2
Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, China.
3
Department of Pathology, University of California, San Diego, La Jolla, CA.
4
Department of Neuroscience, University of California, San Diego, La Jolla, CA.
5
Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
6
Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA xuh@sbpdiscovery.org.

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 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.

PMID:
29114064
PMCID:
PMC5716044
DOI:
10.1084/jem.20171413
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center