Distinct microglial phenotypes in brain diseases
Ten years ago we promoted the concept that microglial activation is not an all or none process but is highly diverse depending on the type of pathology and time point during the pathologic process. We have, therefore, studied aspects of microglial properties in mouse models of Alzheimer’s Disease, schizophrenia, and glioma. In Alzheimer’s Disease two functions of microglial cells are impaired, namely the phagocytic activity and the ability to respond to a local injury. Phagocytic activity is controlled by P2Y6 receptors and we recently found that also purinergic signaling is impaired. An impairment of phagocytic activity was also found in microglia isolated from a mouse model of schizophrenia. In glioma, microglial and invading monocytes accumulate and these glioma associated brain macrophages (GAMs) phagocytic activity is increased. The GAM phenotype is altered in a very characteristic manner not reflecting the classical M1 or M2 phenotype of activation. We found two mechanisms altered in GAMs which helped to promote glioma growth, namely the upregulation of metalloproteases MT1/MMP and MMP9. This supports the hypothesis that microglial cells can obtain diverse phenotypes depending on the pathologic state.