Microglia as a critical player in both developmental and late-life CNS pathologies

Abstract

Microglia, the tissue-resident macrophages of the brain, are attracting increasing attention as key players in brain homeostasis from development through aging. Recent works have highlighted new and unexpected roles for these once-enigmatic cells in both healthy central nervous system function and in diverse pathologies long thought to be primarily the result of neuronal malfunction. In this review, we have chosen to focus on Rett syndrome, which features early neurodevelopmental pathology, and Alzheimer’s disease, a disorder associated predominantly with aging. Interestingly, receptor-mediated microglial phagocytosis has emerged as a key function in both developmental and late-life brain pathologies. In a mouse model of Rett syndrome, bone marrow transplant and CNS engraftment of microglia-like cells were associated with surprising improvements in pathology—these benefits were abrogated by block of phagocytic function. In Alzheimer’s disease, large-scale genome-wide association studies have been brought to bear as a method of identifying previously unknown susceptibility genes, which highlight microglial receptors as promising novel targets for therapeutic modulation. Multi-photon in vivo microscopy has provided a method of directly visualizing the effects of manipulation of these target genes. Here, we review the latest findings and concepts emerging from the rapidly growing body of literature exemplified for Rett syndrome and late-onset, sporadic Alzheimer’s disease.

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

“…In addition, a large number of microglia were excessively activated, exhibiting amoeba-like shape in aged APP/PS1 mice. Although phagocytic microglia can facilitate Aβ degradation and clearance, protecting adjacent neuronal elements, they may also produce a variety of inflammatory factors, causing neurotoxic effects (Derecki et al 2014;Mhatre et al 2015). Therefore, functional impairment of glial cells and microglia may act as a key player in the late stages of AD and protect their functions could serve as an effective strategy against moderate-to-severe AD (Osborn et al 2016).…”

Patterns of Microglial Cell Activation in Alzheimer Disease and Frontotemporal Lobar Degeneration

“…Resting microglia are characterized by a small cell body and ramified processes with a weak expression of associated cell surface marker antigens [19]. This “ramified” microglial cell phenotype is seen when no apparent tissue pathology is present (Fig.…”

Tumor infiltrating immune cells in gliomas and meningiomas

“…In turn, perivascular macrophages participate in antigen-presentation at the BBB, they have a high turnover rate and they are constitutively replenished by circulating monocytes (31,32). In contrast, parenchymal microglia are differentiated tissue macrophages which are supposed to take up residency in the brain during embryonic development (28,33).…”

“…Thus, parenchymal microglial cells are considered to be CNS resident macrophages (28,29). Myeloid cells which populate other brain compartments are generally referred to as macrophages, prefixed with their localization, e.g.…”