Figure 3

Mechanisms of Tat neurotoxicity. (1) Tat binds to the NMDA receptor and drives the phosphorylation of an intracellular NMDAR subunit, causing excess opening of cation channels and toxic accumulation of calcium [62]. (2) When applied to neurons, Tat is able to induce the activation of PLC and drive the IP3-mediated release of intracellular calcium from ER stores, further contributing to calcium toxicity and apoptosis [63]. (3) Tat can bind to LRP receptors, and be taken up as part of a macromolecular complex including NMDAR and neuronal nitric oxide synthase (nNOS) that induces cellular apoptosis [65]. Tat can also drive the internalization of the LRP receptor, reducing the uptake of LRP receptor ligands amyloid-β peptide and Apolipoprotein E, which may contribute to systemic neuronal dysfunction [64]. (4) Tat interferes with the activity of dopamine transporter, diminishing the reuptake of dopamine by pre-synaptic neurons and interfering with signal transmission [67].