Editors' ChoiceAlzheimer’s Disease

GALvanizing Alzheimer’s disease therapy to combat the inflamed brain

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Science Translational Medicine  08 May 2019:
Vol. 11, Issue 491, eaax8310
DOI: 10.1126/scitranslmed.aax8310

Abstract

Galectin-3 is elevated in patients with Alzheimer’s disease (AD), and its deletion reduces neuroinflammation and β-amyloid burden in a mouse model of AD.

Widespread neuroinflammation has been recently identified as hallmark of Alzheimer’s disease (AD). Microglia, the primary immune cells in the central nervous system, are subverted in disease and promote this toxic proinflammatory milieu. A study by Boza-Serrano and colleagues now indicates that the sugar-binding protein Galectin 3 (Gal3) is key for microglia-mediated inflammation in AD.

The authors first showed that GAL3 expression was ten times higher in the brains of patients with AD compared with healthy controls, and it appeared confined to microglia located around β-amyloid (Aβ) plaques. Similarly, in an AD mouse model, GAL3 levels increased with age and it was detectable specifically in plaque-neighboring microglia. Multiple proinflammatory genes were highly transcribed in AD mice, but cross-breeding them to mice lacking Gal3 reduced the transcription of a subset of those. Triggering receptor expressed on myeloid cells 2 (TREM2) signaling, causally linked to AD, was amongst the pathways dependent on Gal3; the authors confirmed that GAL3 could trigger TREM2 signaling, and they also showed that most TREM2-labeled microglia expressed GAL3. Through ultrastructural microscopy and fluorescent anisotropy, they assessed that GAL3 and TREM2 physically interact and thus nominated GAL3 as a putative TREM2 ligand. Microglia activation was reduced in AD mice lacking Gal3, especially around Aβ plaques. At early stages of the disease, Gal3-lacking AD mice had lower Aβ plaque numbers and improved cognitive performances. Interestingly, coinjection of GAL3 and monomeric Aβ, but not monomeric Aβ alone, into the brains of wild-type mice led to the appearance of persistent plaques, suggesting that GAL3 may be implicated in Aβ aggregation.

Understanding how Gal3 deletion mitigates Aβ pathology, and whether it also protects against other AD hallmarks, such as synapse and neuronal loss or tau fibrillation, requires further investigation. Given that GAL3 binds different receptors, it will also be important to establish the dependence of GAL3 effects on TREM2 signaling. Nevertheless, since GAL3 inhibitors have been tested in clinical trials and GAL3 is crucial for microglia activation, results from this study suggest that GAL3 might be a promising target against the pervasive neuroinflammation seen in many neurodegenerative diseases.

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