FIGURE 1.

Proposed mechanism of Tat-induced senescence. (A) Extracellular Tat binds to Connexin 43 and decreases EAAT-2 expression on astrocytes to result in increased extracellular glutamate concentrations. Under normal conditions, glutamate binds to synaptic NMDARs (green) to promote neuroprotective pathways. However, high concentrations of extracellular glutamate will allow glutamate to exit the synaptic cleft and bind to extra-synaptic NMDARs (pink), which promotes excitotoxicity. (B) The interaction depicted in panel (A) has widespread effects on other cells of the CNS. (1) Extracellular glutamate causes cell stress and damage in astrocytes (blue), depicted as loss of foot process, and (2) neurons (gray), depicted as synaptodendritic damage, and (3) causes stress in perivascular macrophages (purple), depicted as an increase in proinflammatory cytokines. Extracellular glutamate also affects (4) endothelial cells (red), causing increased permeability, (5) and release of ROS and pro-inflammatory cytokines (red), which results in (6) recruitment of immune cells (orange) across the BBB and into the CNS, creating a feedback loop of chronic inflammation, and damage. This inflammatory microenvironment will force cells to become senescent, and this will lead to further decreased BBB integrity and production of pro-inflammatory cytokines.