RT Journal Article
SR Electronic
T1 Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 477927
DO 10.1101/477927
A1 Antonio Boza-Serrano
A1 Rocío Ruiz
A1 Raquel Sanchez-Varo
A1 Yiyi Yang
A1 Juan García-Revilla
A1 Itzia Jimenez-Ferrer
A1 Agnes Paulus
A1 Malin Wennström
A1 Anna Vilalta
A1 David Allendorf
A1 Jose Carlos Davila
A1 Christopher Dunning
A1 John Stegmayr
A1 Sebastian Jiménez
A1 The Netherland Brain
A1 Maria Angustias Roca-Ceballos
A1 Victoria Navarro-Garrido
A1 Maria Swanberg
A1 Christine L. Hsieh
A1 Luis Miguel-Real
A1 Elisabet Englund
A1 Sara Linse
A1 Hakon Leffler
A1 Ulf J. Nilsson
A1 Antonia Gutierrez
A1 Guy C. Brown
A1 Javier Vitorica
A1 Jose Luis Venero
A1 Tomas Deierborg
YR 2018
UL http://biorxiv.org/content/early/2018/12/04/477927.abstract
AB 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.