Figure 2.

Schematic diagram shows the mechanisms of blood–brain barrier (BBB) breakdown in normal aging. (1) Oxidative stress increases with age. (2) Oxidative stress triggers endothelial cells ECs to release tumor necrosis factor-α (TNF-α) and consume more ATP. (3) Oxidative stress induces pericytes to release nitric oxides that react with reactive oxygen to further upregulate the oxidative stress causing pericytes apoptosis associated with loss in BBB integrity. (4) During aging, oxidative stress stimulates and activates astrocytes to release cytokines and chemokines that degrade the basement membrane and tight junction leading to BBB impairment. (5) Oxidative stress also activates the microglia to secrete cytokines, chemokines, reactive oxygen, and nitrogen species, causing degradation in BBB integrity. (6) Oxidative stress also induces neurons to release reactive oxygen species (ROS) and calcium ions accumulation that cause to degrade the neurovascular unit (NVU). (7) Toxins freely diffuse to and from the brain, causing neurodegeneration and decline in cognition.