Human immunomodulatory ligand B7-1 mediates synaptic remodeling via the p75 neurotrophin receptor
Nicholas C. Morano, … , Barbara L. Hempstead, Steven C. Almo
Nicholas C. Morano, … , Barbara L. Hempstead, Steven C. Almo
Published September 15, 2022
Citation Information: J Clin Invest. 2022;132(22):e157002. https://doi.org/10.1172/JCI157002.
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Research Article Neuroscience

Human immunomodulatory ligand B7-1 mediates synaptic remodeling via the p75 neurotrophin receptor

Abstract

Cell surface receptors, ligands, and adhesion molecules underlie development, circuit formation, and synaptic function of the central nervous system and represent important therapeutic targets for many neuropathologies. The functional contributions of interactions between cell surface proteins of neurons and nonneuronal cells have not been fully addressed. Using an unbiased protein-protein interaction screen, we showed that the human immunomodulatory ligand B7-1 (hB7-1) interacts with the p75 neurotrophin receptor (p75NTR) and that the B7-1:p75NTR interaction is a recent evolutionary adaptation present in humans and other primates, but absent in mice, rats, and other lower mammals. The surface of hB7-1 that engages p75NTR overlaps with the hB7-1 surface involved in CTLA-4/CD28 recognition, and these molecules directly compete for binding to p75NTR. Soluble or membrane-bound hB7-1 altered dendritic morphology of cultured hippocampal neurons, with loss of the postsynaptic protein PSD95 in a p75NTR-dependent manner. Abatacept, an FDA-approved therapeutic (CTLA-4–hFc fusion) inhibited these processes. In vivo injection of hB7-1 into the murine subiculum, a hippocampal region affected in Alzheimer’s disease, resulted in p75NTR-dependent pruning of dendritic spines. Here, we report the biochemical interaction between B7-1 and p75NTR, describe biological effects on neuronal morphology, and identify a therapeutic opportunity for treatment of neuroinflammatory diseases.

Authors

Nicholas C. Morano, Roshelle S. Smith, Victor Danelon, Ryan Schreiner, Uttsav Patel, Natalia G. Herrera, Carla Smith, Steven M. Olson, Michelle K. Laerke, Alev Celikgil, Scott J. Garforth, Sarah C. Garrett-Thomson, Francis S. Lee, Barbara L. Hempstead, Steven C. Almo

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Figure 4

Recombinant hB7-1–Fc induces synapse remodeling similarly to proNGF.

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Recombinant hB7-1–Fc induces synapse remodeling similarly to proNGF. (A)...
(A) Representative IF images of WT hippocampal neurons treated for 2 hours with proNGF (10 nM), hB7-1–Fc (750 nM), or hB7-2–Fc (750 nM) and stained for actin, PSD95, and MAP2. (B) Quantification of PSD95 puncta density with indicated treatments. Recombinant hB7-1–Fc but not hB7-2–Fc induced a decrease in PSD95 density in cultured neurons, similarly to proNGF treatment. (C) Representative IF images of p75–/– hippocampal neurons treated with proNGF (10 nM), hB7-1–Fc (750 nM), or hB7-2–Fc (750 nM) and stained for actin, PSD95, and MAP2. (D) Quantification of PSD95 puncta density with indicated treatment. Recombinant hB7-1–Fc failed to induce a decrease in PSD95 density in cultured neurons. (E) Representative IF images of WT hippocampal neurons treated with hB7-1–Fc (750 nM) or hB7-2–Fc (750 nM) and stained for actin, GluR1, bassoon, and MAP2. (F) Quantification of bassoon puncta density with indicated treatment. (G) Quantification of GluR1 puncta density with indicated treatment. **P < 0.01, 1-way ANOVA with Dunnett’s multiple-comparisons test. n = 3 independent experiments. Experiments under each condition were performed in triplicate, and 13 to 15 dendritic segments were analyzed per condition. Scale bar: 20 μm. Error bars represent SEM. See also Supplemental Figure 7.