Inhibiting amyloid-β cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design
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Inhibiting the interaction between amyloid-β (Aβ) and a neuronal cell surface receptor, LilrB2, has been suggested as a potential route for treating Alzheimer's disease. Supporting this approach, Alzheimer's-like symptoms are reduced in mouse models following genetic depletion of the LilrB2 homologue. In its pathogenic, oligomeric state, Aβ binds to LilrB2, triggering a pathway to synaptic loss. Here we identify the LilrB2 binding moieties of Aβ (16 KLVFFA 21) and identify its binding site on LilrB2 from a crystal structure of LilrB2 immunoglobulin domains D1D2 complexed to small molecules that mimic phenylalanine residues. In this structure, we observed two pockets that can accommodate the phenylalanine side chains of KLVFFA. These pockets were confirmed to be 16 KLVFFA 21 binding sites by mutagenesis. Rosetta docking revealed a plausible geometry for the Aβ-LilrB2 complex and assisted with the structure-guided selection of small molecule inhibitors. These molecules inhibit Aβ-LilrB2 interactions in vitro and on the cell surface and reduce Aβ cytotoxicity, which suggests these inhibitors are potential therapeutic leads against Alzheimer's disease.
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Compounds ALI6 and 66 block Aβ-LilrB2 interaction, reversing cofilin signaling changes and neurite outgrowth inhibition, protecting neuronal cells from Aβ toxicity.
“Compounds ALI6 (65)586 and 66587 can effectively block this interaction, which reverses the changes in cofilin signaling downstream of LilrB2 and the inhibition of neurite outgrowth, thus protecting neuronal cells from Aβ toxicity.”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [586]
The Results sections on cell-based assays and primary neurons report that ALI6 reduces Aβ–LilrB2-associated binding, restores the Aβ-altered cofilin phosphorylation measure, and protects neurons from Aβ-induced cell death. Our copy does not report that ALI6 reverses inhibition of neurite outgrowth (searched: neurite outgrowth). The separate citation attached to compound 66 is not assessed here. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCompounds inhibiting Aβ/LilrB2 interactions in vitro have been identified, and ALI6 can inhibit Aβ-mediated neurotoxicity in primary neurons.
“Compounds inhibiting Aβ/LilrB2 interactions in vitro have been identified, and potentially bioactive Aβ/LilrB2 inhibitors such as ALI6 can inhibit Aβ-mediated neurotoxicity in primary neurons [94].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [94]
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“585 Compounds ALI6 ( 65 ) 586 and 66 587 can effectively block this interaction, which reverses the changes in co fi lin signaling downstream of LilrB2 and the inhibition of neurite outgrowth, thus protecting neuronal cells from A β toxicity.”
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Additional file 6 of LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions
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Self-citationAdditional file 5 of LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions
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Self-citationAdditional file 3 of LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions
Zhao, P., Xu, Y., Jiang, L.-L., Fan, X., Ku, Z., Li, L., Liu, X., Deng, M., Arase, H., Zhu, J.-J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20098691
Self-citationAdditional file 2 of LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions
Zhao, P., Xu, Y., Jiang, L.-L., Fan, X., Ku, Z., Li, L., Liu, X., Deng, M., Arase, H., Zhu, J.-J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20098688
Self-citationAdditional file 4 of LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions
Zhao, P., Xu, Y., Jiang, L.-L., Fan, X., Ku, Z., Li, L., Liu, X., Deng, M., Arase, H., Zhu, J.-J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20098694
Self-citationAdditional file 10 of LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions
Zhao, P., Xu, Y., Jiang, L.-L., Fan, X., Ku, Z., Li, L., Liu, X., Deng, M., Arase, H., Zhu, J.-J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20098679
Self-citationAdditional file 1 of LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions
Zhao, P., Xu, Y., Jiang, L.-L., Fan, X., Ku, Z., Li, L., Liu, X., Deng, M., Arase, H., Zhu, J.-J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20098685
Self-citationAdditional file 8 of LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions
Zhao, P., Xu, Y., Jiang, L.-L., Fan, X., Ku, Z., Li, L., Liu, X., Deng, M., Arase, H., Zhu, J.-J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20098706
Self-citationAdditional file 7 of LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions
Zhao, P., Xu, Y., Jiang, L.-L., Fan, X., Ku, Z., Li, L., Liu, X., Deng, M., Arase, H., Zhu, J.-J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20098703
Self-citationAdditional file 9 of LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions
Zhao, P., Xu, Y., Jiang, L.-L., Fan, X., Ku, Z., Li, L., Liu, X., Deng, M., Arase, H., Zhu, J.-J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20098712
Self-citationAdditional file 11 of LILRB2-mediated TREM2 signaling inhibition suppresses microglia functions
Zhao, P., Xu, Y., Jiang, L.-L., Fan, X., Ku, Z., Li, L., Liu, X., Deng, M., Arase, H., Zhu, J.-J., et al. (2022) · Figshare · doi:10.6084/m9.figshare.20098682
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- Authors
- Cao, Q., Shin, W. S., Chan, H., Vuong, C. K., Dubois, B., Li, B., Murray, K. A., Sawaya, M. R., Feigon, J., Black, D. L., Eisenberg, D. S., & Jiang, L.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California, Los Angeles (US)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Eisenberg, David S.
- Jiang, Lin
- ORCID
- Venue
- Nature Chemistry
- Published
- 2018-10-08
- Volume
- 10
- Issue
- 12
- Pages
- 1213-1221
- ISSN
- 1755-4330 (ISSN-L)
- 1755-4349
- PMC
- PMC6250578
- OpenAlex
- W2889706274
- Cited by
- 75
- References
- 47
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 10 · 2023: 8 · 2022: 21 · 2021: 9 · 2020: 10 · 2019: 8 · 2014: 1
- FWCI
- 4.63
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-11-12)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- Office of Science
- National Institute on Aging (RF1AG054022)
- National Institute of General Medical Sciences (R01GM114463, P41GM103403)
- National Center for Research Resources (S10RR029205)
- Argonne National Laboratory
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Keywords
- amyloid-beta, LILRB2, Alzheimer's disease, structure-based drug design, small molecule inhibitors, immunoglobulin domains, binding site identification, synaptic loss, amyloid-beta oligomers
- MeSH terms
- Alzheimer Disease, Animals, Cell Survival, Dose-Response Relationship, Drug, Humans, Membrane Glycoproteins, Neurons, Receptors, Immunologic, Structure-Activity Relationship, Drug Design, Molecular Structure, Amyloid beta-Peptides, Mice, Small Molecule Libraries
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