Copyright de los autores.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.- Financiación del Consejo de Investigación Sueca, y el Parque de Investigación "Strong Research Environment MultiPark (Multidisciplinary Research in Parkinson’s and Alzheimer’s Disease" de la Universidad de Lund.
- Bagadilico (consorciado esponsorizado por el Consejo de Investigación Sueca), la Fundación Sueca de Alzheimer, la fundación Sueca del Cerebro, Fundación A.E. Berger Foundation, la fundación Gyllenstiernska Krapperup, la Real Sociedad Fisiográfica, la Fundación Crafoord, Fundación Olle Engkvist Byggmästare, Fundación Wiberg, Fundación G&J Kock, Fundación Stohnes, Asociación Sueca de Demencia y la Facultad de Medicina de la Universidad de Lund.
- Proyectos SAF2015-64171R (MINECO/FEDER, UE)
- Instituto de Salud Carlos III (ISCiii) co-financiado por fondos FEDER de la Unión Europea por proyectos PI15/00796 y PI18/01557 (a AG), PI15/00957 y PI18/01556 (JV).
- CIBERNED “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid (AG y JV)
- Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía Proyecto de Excelencia (CTS2035) (JV y AG).
- Universidad de Málaga referencia PPIT.UMA.27(RSV)
- AV y GCB recibieron fondos de la Iniciativa para Medicina Innovativa ref. 115976 (PHAGO).
- Consejo de Investigación Sueca, Fundación Sueca del Cerebro, Fundación de Alzheimer y Fundación Ahlen (a HL y AF).
- Proyecto de Fundación Knut and Alice Wallenberg (UJN) (KAW 2013.0022) y Consejo de Investigación Sueca (ref. 621-2012-2978)
