Fig. 3

Inflammatory responses in the young and old brain. The BBB is intact in the young brain, reinforced by tight junctions, endothelial cells, pericytes, and astrocytes (blue). During homeostasis, microglia (orange) perform a surveillance role with extended processes. Microglia and astrocytes are activated by an inflammatory event, during which the microglia prepare for phagocytosis to eliminate the inflammatory stimulus, such as during a bacterial infection following an injury. Peripheral immune cells such as monocytes (green) are also able to cross the BBB to enhance phagocytosis and debris clearance in the brain. After the inflammatory event, microglia in the young brain are able to return to their surveillance state. After a lifetime of such events, however, microglia in the aged brain acquire a primed state, where they exhibit persistent low-level inflammation during homeostasis. During aging, the BBB also becomes leaky. Primed microglia are fast to react to inflammatory stimuli, but have a high risk of becoming senescent and unable to perform phagocytosis and clear infection. If the microglia are no longer able to remove the infection, they continue to release inflammatory mediators, leading to increased inflammatory cell migration past the BBB, which is further permeabilized during disease