Microglia in Alzheimer's Disease and Transgenic Models: How Close the Fit?

Abstract

Research on microglia has grown nearly exponentially over the last two decades, 1 fueled in part by the recognition that inflammation plays a role in the pathogenesis of Alzheimer’s disease (AD). 2 Whereas their existence as a distinct central nervous system (CNS) cell type was once debated, it is now widely accepted that microglia are monocyte-derived cells that enter the CNS at early stages of development as highly mobile, ameboid cells that are distributed widely throughout the brain and spinal cord, developing a highly ramified phenotype that eventually forms a uniform reticular array in both gray and white matter. Being related to other cells of the mononuclear phagocytic system they are considered to be poised for activation, each cell policing a discrete and nonoverlapping domain and acting as a sentinel to disruption of the normal homeostasis of the neural tissue. 3 Microglia respond rapidly to subtle alterations not associated with any apparent tissue damage such as spreading electrical depression 4 as well as more severe insults such as anoxic-ischemic injury and neuronal loss associated with a host of degenerative disorders with a sequence of antigenic and morphological changes. The latter form is less ramified, with more abundant cytoplasm in soma and cell processes. It has cell markers, such as class II major histocompatibility antigen, that are barely detectable in the ramified form and is referred to as activated. The full repertoire of ramified microglia is not known, but they appear to be long-lived cells with a limited potential to divide, which contrasts with perivascular macrophages. 5 The latter have a more dynamic life cycle and enter and leave the CNS compartment more readily throughout the life of the individual. The perivascular macrophage, which constitutively express class II major histocompatibility antigen (HLA-DR) participates in the immune response and is fully capable of antigen presentation. 6 The phagocytic potential of the perivascular macrophage is not disputed, but whether ramified microglia are phagocytic cells is debated. Progressive transformation of ramified microglia to macrophages has been shown in a limited number of demyelinating conditions, where it appears that at least some microglia may differentiate into brain macrophages. 3,7