Galectin‑3, a novel endogenous TREM2 ligand, detrimentally regulates infammatory response in Alzheimer’s disease

Boza Serrano, Antonio; Ruíz Laza, Rocio; Sánchez Varo, Raquel María; García Revilla, Juan; Yang, Yiyi; Jiménez Ferrer, Itzia; Jiménez Muñoz, Sebastián; Roca Ceballos, María Angustias; Navarro Garrido, Victoria; Real Navarrete, Luis Miguel; Vitorica Ferrández, Francisco Javier; Venero Recio, José Luis; Deierborg, Tomas

doi:10.1007/s00401-019-02013-z

Galectin‑3, a novel endogenous TREM2 ligand, detrimentally regulates infammatory response in Alzheimer’s disease

Boza Serrano, Antonio; Ruíz Laza, Rocio; Sánchez Varo, Raquel María; García Revilla, Juan; Yang, Yiyi; Jiménez Ferrer, Itzia; Jiménez Muñoz, Sebastián; Roca Ceballos, María Angustias; Navarro Garrido, Victoria; Real Navarrete, Luis Miguel; Vitorica Ferrá

Published: 2019
Publisher: Springer
DOI: 10.1007/s00401-019-02013-z
Repository: idus.us.es
Language: en

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.

Full text

Vol.:(0123456789) 1 3 Acta Neuropathologica (2023) 145:509–510 https://doi.org/10.1007/s00401-023-02549-1 CORRECTION Correction to: Galectin‑3, anovel endogenous TREM2 ligand, detrimentally regulates inflammatory response inAlzheimer’s disease AntonioBoza‑Serrano1 · RocíoRuiz2· RaquelSanchez‑Varo3,13· JuanGarcía‑Revilla2· YiyiYang1· ItziaJimenez‑Ferrer11· AgnesPaulus1· MalinWennström5· AnnaVilalta4· DavidAllendorf4· JoseCarlosDavila3,13· JohnStegmayr9· SebastianJiménez2,13· MariaA.Roca‑Ceballos2· VictoriaNavarro‑Garrido2,13· MariaSwanberg11· ChristineL.Hsieh12· LuisM.Real7· ElisabetEnglund8· SaraLinse6· HakonLeffler9· UlfJ.Nilsson10· GuyC.Brown4· AntoniaGutierrez3,13· JavierVitorica2,13· JoseLuisVenero2· TomasDeierborg1 Published online: 15 February 2023 © The Author(s) 2023 Correction to: Acta Neuropathologica (2019) 138:251–273 https://doi.org/10.1007/s00401-019-02013-z In this article author would like to make few changes in the article text. The corrections are given below. 1. In Materials and methods section for Immunofluorescence of human sections: In the sentence: “The sections were then washed (3 × 15min) in 0.1M KPBS, after which they were incubated in blocking buffer (5% goat serum blocking with 0.1M KPBS and 0.025% Triton-X) for at least 1h with gentle agitation.” Action: Change the word Goat for Donkey. 2. In Material and methods section for ELISA plates: In the paragraph: “The detection ranges of the different cytokines measured were as follows: IL1β (1670–0.408pg/mL), IL4 (1660–0.405pg/mL), IL12 (32,200–7.86pg/mL), IL10 The original article can be found online at https:// doi. org/ 10. 1007/ s00401- 019- 02013-z. * Antonio Boza-Serrano antonio.boza_ser[email protected] * Jose Luis Venero jl[email protected] * Tomas Deierborg [email protected] 1 Department ofExperimental Medical Science, Experimental Neuroinflammation Laboratory, Lund University, 22184Lund, Sweden 2 Departamento de Bioquímica y Biología Molecular, Instituto de Biomedicina de Sevilla (IBiS, HUVR/CSIC/Universidad de Sevilla), Universidad de Sevilla, Seville, Spain 3 Departamento de Biología CelularGenética y Fisiología, Instituto de Investigación Biomédica de Málaga (IBIMA), Facultad de Ciencias, Universidad de Málaga, Málaga, Spain 4 Department ofBiochemistry, University ofCambridge, Cambridge, UK 5 Clinical Memory Research Unit, Department ofClinical Sciences Malmö, Lund University, Malmö, Sweden 6 Department ofBiochemistry andStructural Biology, Lund University, Lund, Sweden 7 Unidad Clínica de Enfermedades Infecciosas y Microbiología, Hospital Universitario de Valme, Seville, Spain 8 Division ofOncology andPathology, Department ofClinical Sciences, Lund University, Lund, Sweden 9 Department ofLaboratory Medicine, Division ofMicrobiology, Immunology andGlycobiology (MIG), Lund University, Lund, Sweden 10 Department ofChemistry, Centre forAnalysis andSynthesis, Lund University, Lund, Sweden 11 Translational Neurogenetics Unit, Department ofExperimental Medical Science, Wallenberg Neuroscience Center, Lund University, 22184Lund, Sweden 12 Immunology Section, Department ofMedicine, San Francisco VA Medical Center, UCSF School ofMedicine, 4150 Clement St. 111R, SanFrancisco, CA94121, USA 13 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain 510 Acta Neuropathologica (2023) 145:509–510 1 3 (3410–0.833 pg/mL), IFN-γ (938–0.229 pg/mL), IL2 (2630–0.642 pg/mL), IL5 (967–0.236 pg/mL), IL6 (5720–1.40pg/mL), KC/GRO (1980–0.483pg/mL) and TNF-α (627–0.153pg/mL). The Aβ40 detection range was 15,100–3.69pg/mL, and the Aβ42 detection range was 2280–0.557pg/mL. ELISA plates from R&D (DY008 and DY1197-05) were used to measure the levels of gal3 (detection range 1000–15.6pg/mL) in culture media.” Action: Write “IL8 regarded as human functional homolog to rodent KC”between brackets next to KC/GRO. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.