Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease

DOI: http://doi.org/10.1101/477927 Journal: E-pub date: 1 Aug 2018 Authors: A Boza-Serrano, R Ruiz, R Sanchez-Varo, Y Yang, J García-Revilla, I Jimenez-Ferrer, A Paulus, M Wennström, A Vilalta, D Allendorf, JC Davila, C Dunning, J Stegmayr, S Jiménez, MA Roca-Ceballos, V Navarro-Garrido, M Swanberg, C Hsieh, L Miguel-Real, E Englund, S Linse, H Leffler, U Nilsson, A Gutierrez, G Brown, J Vitorica, JL Venero, T Deierborg, The Netherland Brain

Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease

Abstract:

ABSTRACT Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, intraneuronal tau neurofibrillary tangles 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 to 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 demonstrated the requirement of gal3 to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Electron microscopy of gal3 in AD mice demonstrated i) a preferential expression of gal3 by plaque-associated microglia, ii) its presence in the extracellular space and iii) its association to Aβ plaques. Low concentrations (1 nM) of pure gal3 promoted cross-seeding fibrilization of pure Aβ. Importantly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of insoluble Aβ aggregates that were absent when gal3 was lacking. High-resolution microscopy (STORM) demonstrated close co-localization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 CRD domain. Furthermore, gal3 stimulated the TREM2-DAP12 signaling pathway. In conclusion, we provide evidence that gal3 is a central regulator of microglial immune response in AD. It drives proinflammatory activation and Aβ aggregation, as well as acting as an endogenous ligand to TREM2, a key receptor driving microglial response under disease conditions. Gal3 inhibition may, hence, be a potential pharmacological approach to counteract AD.