SORLA attenuates EphA4 signaling and amyloid β–induced neurodegeneration
Open accessAbstract
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.
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An AD-associated mutation in SORLA impairs the interaction between EphA4 and SORLA.
“An AD-associated mutation in SORLA impairs the interaction between EphA4 and SORLA.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [80]
SORLA interactions with the EphA4 receptor attenuate EphA4 activation in response to Aβ exposure.
“Our recent work provides a new insight into EphA4-mediated Aβ toxicity; SORLA interactions with the EphA4 receptor can consequently attenuate EphA4 activation in response to Aβ exposure.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [80]
Greater amounts of active EphA4 are evident in AD brain.
“Moreover, deposition of EphA4 is observed in regions surrounding senile plaques in human hippocampus [79], and greater amounts of active EphA4 are evident in AD brain [80].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [80]
EphA4 is activated in human AD brain, and EphA4 activation correlates with decreased EphA4/SORLA interaction.
“In addition, we found that EphA4 is activated in human AD brain, and EphA4 activation correlates with decreased EphA4/SORLA interaction [80].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [80]
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Amyloid Beta in Alzheimer's Disease: Mechanisms, Biomarker Potential, and Therapeutic Targets
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Self-citationEndo‐Lysosomal Network Disorder Reprograms Energy Metabolism in SorL1 ‐Null Rat Hippocampus
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SORLA upregulation suppresses global pathological effects in aged tauopathy mouse brainPreprint
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Self-citationAdditional file 9 of Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
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Self-citationAdditional file 8 of Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
Zhu, B., Liu, Y., Hwang, S. Y., Archuleta, K., Huang, H., Campos, A. R., Murad, R., Piña-Crespo, J., Xu, H., & Huang, T. Y. (2022) · Figshare · doi:10.6084/m9.figshare.20861158
Self-citationAdditional file 3 of Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
Zhu, B., Liu, Y., Hwang, S. Y., Archuleta, K., Huang, H., Campos, A., Murad, R., Piña-Crespo, J., Xu, H., & Huang, T. Y. (2022) · Figshare · doi:10.6084/m9.figshare.20861137
Self-citationAdditional file 6 of Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
Zhu, B., Liu, Y., Hwang, S. Y., Archuleta, K., Huang, H., Campos, A., Murad, R., Piña-Crespo, J., Xu, H., & Huang, T. Y. (2022) · Figshare · doi:10.6084/m9.figshare.20861149
Self-citationAdditional file 5 of Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
Zhu, B., Liu, Y., Hwang, S. Y., Archuleta, K., Huang, H., Campos, A., Murad, R., Piña-Crespo, J., Xu, H., & Huang, T. Y. (2022) · Figshare · doi:10.6084/m9.figshare.20861146
Self-citationAdditional file 4 of Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
Zhu, B., Liu, Y., Hwang, S. Y., Archuleta, K., Huang, H., Campos, A., Murad, R., Piña-Crespo, J., Xu, H., & Huang, T. Y. (2022) · Figshare · doi:10.6084/m9.figshare.20861143
Self-citationAdditional file 7 of Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
Zhu, B., Liu, Y., Hwang, S. Y., Archuleta, K., Huang, H., Campos, A., Murad, R., Piña-Crespo, J., Xu, H., & Huang, T. Y. (2022) · Figshare · doi:10.6084/m9.figshare.20861152
Self-citationAdditional file 2 of Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
Zhu, B., Liu, Y., Hwang, S. Y., Archuleta, K., Huang, H., Campos, A., Murad, R., Piña-Crespo, J., Xu, H., & Huang, T. Y. (2022) · Figshare · doi:10.6084/m9.figshare.20861134
Self-citationAdditional file 1 of Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
Zhu, B., Liu, Y., Hwang, S. Y., Archuleta, K., Huang, H., Campos, A., Murad, R., Piña-Crespo, J., Xu, H., & Huang, T. Y. (2022) · Figshare · doi:10.6084/m9.figshare.20861131
Self-citationSORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain
Huang, H., Shi, C. H., Yang, W., Piña-Crespo, J., Bhatnagar, J., Curatolo, J., Murad, R., Shah, P., Campos, A., Houser, A. M., et al. (2026) · Science Advances · doi:10.1126/sciadv.aed6825 · Cited by 1 · see citing works
Self-citationDistinct competitive and allosteric binding modes of nanobodies targeting EphA4
Jiang, H., Ding, L., Yang, C., Guo, G., Zhong, C., Ma, Z., Zhu, H., Zhang, J., Luo, Y., Liu, Z., et al. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.113394
Sun, J., Gao, G., Wang, S., Li, S., Tang, J., Liu, H., & Tang, T.-S. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02776-4
- Authors
- 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., & Xu, H.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- University of California San Diego (US)
- Max Delbrück Center (DE)
- Corresponding author
- Xu, Huaxi
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2017-11-07
- Volume
- 214
- Issue
- 12
- Pages
- 3669-3685
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC5716044
- OpenAlex
- W2767584725
- Cited by
- 50
- References
- 56
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 8 · 2022: 15 · 2021: 4 · 2020: 3 · 2019: 8 · 2018: 2
- FWCI
- 2.63
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- Funders
- National Institutes of Health (R01AG021173, R01AG038710, R01AG044420, R01NS046673, R01AG18440, R01AG5131, R01AG11385, R01NS076411, R01NS087070)
- Alzheimer’s Association
- The Tanz Family Funds
- Cure Alzheimer’s Fund
- Shiley-Marcos Alzheimer’s Disease Research Center
- University of California, San Diego (ADRC 2015 59226)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- SorLA, EphA4, ephrin-A1, amyloid-beta oligomers, Alzheimer's disease, synaptic dysfunction, postsynaptic density, long-term potentiation, memory impairment, synaptotoxicity, receptor tyrosine kinase, cognitive impairment
- MeSH terms
- Protein Domains, Alzheimer Disease, Animals, Humans, Ligands, Mice, Inbred BALB C, Mice, Transgenic, Mutation, Nerve Degeneration, Protein Binding, Receptors, LDL, Synapses, Amyloid beta-Protein Precursor, Long-Term Potentiation, Growth Cones, LDL-Receptor Related Proteins, Membrane Transport Proteins, Receptor, EphA4, Ephrins, HEK293 Cells
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