Vilalta, A. | bioRxiv Science

bioRxiv2019

TET2 regulates the neuroinflammatory response in microglia

Epigenetic mechanisms regulate distinct aspects of the inflammatory response in various immune cell types. Despite the central role for microglia, the resident macrophages of the brain, in neuroinflammation and neurodegeneration little is known about their epigenetic regulation of the inflammatory response. Here, we show that Ten-eleven translocation 2 (TET2) methylcytosine dioxygenase expression is increased in microglia upon stimulation with various inflammogens through a NF-{kappa}B-dependent pathway. We found that TET2 regulates early gene transcriptional changes that lead to early metabolic alterations, as well as a later inflammatory response independently of its 5mC oxidation activity at the affected genes. We further show that TET2 regulates the proinflammatory response in microglia induced by intraperitoneal injection of LPS in vivo. We observed that microglia associated to amyloid {beta} plaques, recently defined as disease-associated microglia, expressed TET2 in brain tissue from individuals with Alzheimers disease (AD) and in 5xFAD mice. Collectively, our findings show that TET2 plays an important role in the microglial inflammatory response, and suggest TET2 as a potential target to combat neurodegenerative brain disorders.

neuroscience↗

bioRxiv2018

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

Alzheimers disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (A{beta}) 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 Alzheimers 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 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 A{beta}. Gal3 deletion decreased the A{beta} 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 A{beta} plaques. Low concentrations (1 nM) of pure gal3 promoted cross-seeding fibrilization of pure A{beta}. Importantly, a single intrahippocampal injection of gal3 along with A{beta} monomers in WT mice was sufficient to induce the formation of insoluble A{beta} 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 A{beta} 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.

neuroscience↗