25 March 2015. Vol.6 No.2
Aβ-mediated increases in extracellular glutamate and the resulting excitotoxicity. (1) Aβ increases presynaptic release of glutamate. (2) Aβ elevates astrocytic calcium via stimulation of astrocytic α7 nicotinic receptors, resulting in astrocytic glutamate release via an unknown mechanism. (3) Aβ decreases glutamate clearance from the synapse, thereby prolonging the duration of glutamate in the synapse and potentially resulting in the spread of glutamate to neighboring synapses. (4) Prolonged activation of S-NMDARs and AMPARs resulting from increased extracellular glutamate is predicted to cause desensitization and internalization of NMDA/AMPA, resulting in synaptic depression. (5) Glutamate spillover activates E-NMDARs, resulting in multiple deleterious downstream events, including an increase in tau kinase activity, cell death, and blockade of long-term potentiation (LTP) and CREB phosphorylation (pCREB).