Microglial Cell Dysregulation in the Aged Brain and Neurodegeneration

For several decades, microglia were considered to be subordinated to neurons. However, growing evidence indicates that microglia play key roles in the normal functioning of the nervous system, as well as in age-dependent changes and neurodegenerative diseases. As the brain ages, microglia acquire a phenotype that can be increasingly inflammatory and cytotoxic (dysfunctional microglia), generating a hostile environment for neurons. There is mounting evidence that this process facilitates the development of neurodegenerative diseases, for which the greatest risk factor is age. In neurodegenerative diseases, the abnormal inflammatory response can depend on the impairment of the endogenous activation control of aging microglia that potentiate the release of potentially detrimental factors such as cytokines and oxidative stress mediators. This chapter will discuss key aging-dependent changes occurring in microglia, the inflammatory and oxidative environment they establish, their impaired regulation, and their interaction and effect on neurons. In addition, the role of complement in the neuron-microglia interaction and their modeling of neural circuits through microglia-mediated phagocytosis in development will be highlighted, as well as the growing evidence on its contribution in neurodegenerative processes.