The Role of TREM2 and the Responses Mediated by Galectin-3 During Age-Related Myelin Degeneration

Abstract

Aging is the greatest known risk factor for various neurodegenerative diseases. Myelin degeneration is an early pathological indicator of these diseases and normal part of aging; albeit, to a lesser extent. Despite this, little is known about how age-related degeneration could contribute to and impact development of neurodegenerative disease. Microglia participate in a variety of white matter events from demyelination to remyelination. The microglial innate immune receptor triggering receptor expressed on myeloid cells 2 (TREM2) has been implicated in regulating (de)myelination. We found in response to demyelination, TREM2 is required for large volumes of myelin debris and during extended periods of phagocytosis. In addition to lysosomal regulation, we showed TREM2 can modify the ER stress response prior to overt myelin debris preventing early microglial dysfunction. We found TREM2 is necessary for remyelination by recruiting reparative glia and mediating signaling that promotes OPC differentiation/maturation. One of the signaling factors involved, the β-galactosidase-binding protein galectin-3 (gal-3), was recently identified as a ligand for TREM2, however little is known about this interaction in the context of aging or neurodegenerative disease. Treating microglia with a pharmacological gal-3 inhibitor, we found overlapping functional deficits with Trem2-deficient microglia during myelin phagocytosis. These shared deficits included impaired myelin uptake, altered lysosomal function, ER stress, and lipid droplet accumulation that were rescued inTrem2-deficient microglia with the addition of recombinant gal-3. RNA-seq analyses revealed common genes and pathways affected that importantly included genes associated with the integrated stress response. Taken together, these data suggest Gal-3 mediates and throttles the TREM2-dependent stress response during age-related myelin degeneration. Further, it provides support for targeting TREM2 function early to augment reparative signaling preventing overt debris accumulation and/or promoting gal-3 to alleviate stress pathways that can lead to premature microglial dysfunction and onset of pathology.