Microglial exosomes: taking messaging to new spheres

The negative impact of neurodegenerative conditions on life quality has been increasing due to the lengthening of human lifespan. It is now well appreciated that both neurons and glia are fundamentally involved in neurodegenerative diseases. Microglia are essential for brain homeostasis through clearance of cellular debris, releasing neurotrophic factors as well as pruning of synapses. Studies have linked many of the genetic mutations that increase the risk for neurodegenerative diseases, such as Alzheimer’s disease, to a predominant expression of these genes by microglia. Variants in triggering receptor expressed on myeloid cell 2 (TREM2) gene are among the high-risk factors for lateonset Alzheimer’s disease. TREM2 is a transmembrane protein and important for cell survival, phagocytosis and proliferation. Polyanionic ligands, bacterial lipopolysaccharide (LPS) and phospholipids, as well as lipoproteins, including apolipoprotein E, low-density lipoprotein and amyloid-beta A4 protein, have been identified as endogenous ligands to TREM2. Ligand binding induces phosphorylation of the adaptor protein DAP12 and downstream signalling via several signalling cascades including activation of phosphatidylinositol 3-kinase and mitogen-activated protein kinases and the elevation of intracellular Ca2þ, which regulate a multitude of cellular functions. The R47H variant is located in the protein’s extracellular immunoglobulin domain and thought to reduce the receptor’s binding affinity and is therefore considered a partial loss-of-function. Comparison of TREM2-deficient and R47H mutant rodent microglia to wild-type cells showed differential expression of several genes during homeostatic conditions. The effect of TREM2 deficiency increased after exposure of microglia to Alzheimer’s disease-associated mutated microtubule-associated protein tau (MAPT) or PSEN/APP forms indicating an altered behaviour of the mutant cells in pathological conditions. Comparison of murine and human microglia transcriptome revealed differences in gene expression and aberrant splicing between Exons 1 and 2, highlighting the importance to study microglia function directly in human cells. Derivation of neural and immune cells from induced pluripotent stem cells (iPSCs) allows the use of patient derived cells that carry genetic information to create tissue models for neurological conditions. The derivation of human iPSC-derived microglia-like cells has been designed to recapitulate microglial embryonic development. iPSC-derived microglia show several features of in vivo human microglia, including ramified morphology, expression of categorical microglial markers (such as IBA1, CX3CR1, CD11b, CD45, TMEM119) and typical microglial functions such as phagocytosis, process motility and cytokine response upon stimulation. Besides physical contact, metabolic support and cytokine release, exosomes and extracellular vesicles (EVs) have recently emerged as an important mechanism for intercellular communication in the central nervous system. Microglial EVs have been implied in acute inflammatory responses through the release of IL1b, regulation of neuronal synaptic activity, and as a source of energy substrates for neurons. In this issue, Mallach et al. present new data that focuses on the possible role of exosomes in neurodegenerative conditions. The authors took advantage of iPSCs established from patients carrying the TREM2 R47H mutation and differentiated the cells to microglia lineage. Previous analysis from the same workgroup showed reduced metabolic activity of microglia carrying the TREM2 mutation. In the current follow-up study the authors tested whether the TREM2 mutation can alter the content of microglia-released exosomes and if the exosomes have altered function. The TREM2 R47H mutant cells were found to have reduced exosome release and altered exosomal peptide content including nine proteins related to negative regulation of transcription and metabolism (Fig. 1).