Journal
ACTA NEUROPATHOLOGICA
Volume 138, Issue 2, Pages 251-273Publisher
SPRINGER
DOI: 10.1007/s00401-019-02013-z
Keywords
Alzheimer's disease (AD); Galectin-3; TREM2; Microglia; Inflammation; Amyloid aggregation
Categories
Funding
- Swedish Research Council [621-2012-2978]
- Strong Research Environment MultiPark (Multidisciplinary Research in Parkinson's and Alzheimer's Disease at Lund University)
- (Swedish Research Council)
- Swedish Alzheimer's Foundation
- Swedish Brain Foundation
- A. E. Berger Foundation
- Gyllenstiernska Krapperup Foundation
- Royal Physiographic Society
- Crafoord Foundation
- Olle Engkvist Byggmastare Foundation
- Wiberg Foundation, G& J Kock Foundation
- Stohnes Foundation
- Swedish Dementia Association
- Medical Faculty at Lund University [SAF2015-64171R]
- Spanish MINECO/FEDER
- Instituto de Salud Carlos III (ISCiii) of Spain - FEDER funds from European Union [PI15/00796, PI18/01557, PI15/00957, PI18/01556]
- CIBERNED
- Consejeria de Economia, Innovacion, Ciencia y Empleo, Junta de Andalucia Proyecto de Excelencia [CTS-2035]
- Malaga University [B1.2017/26]
- Innovative Medicines Initiative 2 Joint Undertaking [115976]
- CIBERNED Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid (Spain)
- Alzheimer Foundation
- Ahlen Foundation
- Knut and Alice Wallenberg Foundation [KAW 2013.0022]
- MRC [MR/L010593/1] Funding Source: UKRI
Ask authors/readers for more resources
Alzheimer's disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (A beta) 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 A beta 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 A beta. Gal3 deletion decreased the A beta burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with A beta monomers in WT mice was sufficient to induce the formation of long-lasting (2months) insoluble A beta 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available