Microglia are the brain macrophages that respond to a variety of CNS injuries. There are three states of microglia: (1) resting, which are highly ramified cells, (2) activated microglia, which are cells responding to injury with morphological (enlarged cell bodies, contraction of processes) and immunophenotypic changes as well as proliferation, and (3) phagocytic microglia, which are full-blown brain macrophages with amoeboid morphology and expression of a number of immunomolecules. Activated microglia retract their processes followed by a rounding of the cell body. This is accompanied by increased expression of complement receptor 3. MHC class I and II antigens are up-regulated on the microglial cell surface, which enables the microglia to interact with immunocompetent cells such as T-cells. Once activated, phagocytic microglia are able to remove debris. The phagocytic microglia invade the area of damage and appear over a period of days, depending on the nature, severity, and location of the CNS damage. However, the process of debris removal can take from days to many weeks. This is in contrast to damage in the PNS, where macrophages have cleared debris within 2 weeks. As well as having a role in acute CNS injury, microglia may also play a role in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. These conditions are characterized by the selective loss of neurons in distinct areas of the brain, areas in which microglia are activated. In Alzheimer plaques containing amyloid-b protein, microglia are present in the center of these plaques. It has been shown that amyloid-b protein precursor can activate microglia, which may act to enhance their toxicity.

Microglia are also involved in CNS autoimmunity and are activated by inflammatory signals such as LPS and interferon. Microglia are involved in HIV encephalitis, and although it is not clear how HIV interacts with microglia, it is thought that the HIV virus enters the CNS parenchyma hidden in infected monocytes and may subsequently spread to microglia.

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