FIGURE 8.

A schematic diagram showing hypothetic cascades through which Aβ oligomers induce surface AMPAR loss leading to inhibition of synaptic efficacy. Binding of Aβ oligomers to receptors on dendritic spines triggers activation of calcineurin (PP2B), probably via Ca²⁺/calmodulin-dependent kinase II (CaMKII) activity. The calcineurin activity activates the clathrin-dependent endocytosis of AMPARs and/or NMDARs via the involvement of dynamin. Activation of the group I metabotropic glutamate receptors (mGluR1/5) is involved in this cascade, which in turn facilitates the internalization of AMPARs. On the other hand, the interaction of Aβ oligomers with GluR2 may potentially interfere with the Ca²⁺ impermeability of the AMPAR channel leading to increased voltage-dependent Ca²⁺ influx, thus generating aberrant Ca²⁺ toxicity. The abnormal Ca²⁺ signals could enhance the internalization of dendritic AMPAR. Removal of the surface AMPAR and NMDA lead to LTD and reduced spine numbers. If LTD and loss of spine structure persist, the resulting synaptic transmission failure would lead to memory impairment.