Ricerc@Sapienza

The continuous crosstalk between microglia and neurons is required for microglia housekeeping functions and contributes to brain homeostasis. Through these exchanges, microglia take part in crucial brain functions, including development and plasticity. The alteration of neuron-microglia communication contributes to brain disease states with consequences, ranging from synaptic function to neuronal survival. This review focuses on the signaling pathways responsible for neuron-microglia crosstalk, highlighting their physiological roles and their alteration or specific involvement in disease.

Microglia are the resident immune cells of the central nervous system (CNS). In the last year, the improvements in the transgenic mouse technologies and imaging techniques have shed light on microglia functions under physiological conditions. Microglia continuously scan the brain parenchyma with their highly motile processes, maintaining tissue homeostasis and participating in neuronal circuits refinement.

Deficient neuron-microglia signaling during brain development is associated with abnormal synaptic maturation. However, the precise impact of deficient microglia function on synaptic maturation and the mechanisms involved remain poorly defined. Here we report that mice defective in neuron-to-microglia signaling via the fractalkine receptor (Cx3cr1 KO) show reduced microglial branching and altered motility and develop widespread deficits in glutamatergic neurotransmission.

Glioblastoma is the most aggressive and deadly brain tumor, with low disease-free period even after surgery and combined radio and chemotherapies. Among the factors contributing to rapid tumor growth in the brain are the elevated proliferation and invasion rate, and the ability to induce a local immunosuppressive environment. The intermediate-conductance Ca2+-activated K+ channel KCa3.1 is expressed on glioblastoma cells and in tumor-infiltrating cells. In tumor cells, the functional expression of KCa3.1 is important to modulate cell invasion and proliferation.

Extracellular-released vesicles (EVs), such as microvesicles (MV) and exosomes (Exo)
provide a new type of inter-cellular communication, directly transferring a ready to use
box of information, consisting of proteins, lipids and nucleic acids. In the nervous
system, EVs participate to neuron-glial cross-talk, a bidirectional communication
important to preserve brain homeostasis and, when dysfunctional, involved in several
CNS diseases. We investigated whether microglia-derived EVs could be used to transfer

As a consequence of an increasingly aging population, the number of people affected by neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, is rapidly increasing. Although the etiology of these diseases has not been completely defined, common molecular mechanisms including neuroinflammation, excitotoxicity and mitochondrial dysfunction have been confirmed and can be targeted therapeutically.

In glioma, microglia and infiltrating macrophages are exposed to factors that force them to produce cytokines and chemokines, contributing to tumor growth and maintaining a pro-tumorigenic, immunosuppressed microenvironment. We demonstrate that housing glioma-bearing mice in enriched environment (EE) reverts the immunosuppressive phenotype of infiltrating myeloid cells, by modulating inflammatory gene expression. Under these conditions, branching and patrolling activity of myeloid cells is increased, and their phagocytic activity is promoted.

Background

Mutations of Fused in sarcoma (FUS), a ribonucleoprotein involved in RNA metabolism, have been found associated with both familial and sporadic cases of amyotrophic lateral sclerosis (ALS). Notably, besides mutations in the coding sequence, also mutations into the 3′ untranslated region, leading to increased levels of the wild-type protein, have been associated with neuronal death and ALS pathology, in ALS models and patients.

In amyotrophic lateral sclerosis (ALS), immune cells and glia contribute to motor neuron (MN) degeneration. We report the presence of NK cells in post-mortem ALS motor cortex and spinal cord tissues, and the expression of NKG2D ligands on MNs. Using a mouse model of familial-ALS, hSOD1G93A, we demonstrate NK cell accumulation in the motor cortex and spinal cord, with an early CCL2-dependent peak. NK cell depletion reduces the pace of MN degeneration, delays motor impairment and increases survival. This is confirmed in another ALS mouse model, TDP43A315T.