Molecular pathways of oligomeric Aβ mediated synaptic dysfunction. Oligomeric Aβ (oAβ) can induce calcium dyshomeostasis, trigger activation of caspase 3, or modulate the activity of NMDARs either directly or through intermediate molecules (shown as X) involved in the trafficking of NMDAR (e.g. EphB2). Activation of different subtypes of NMDA receptors may trigger different intrasynaptic pathways. Activation of NR2A containing NMDARs may lead to high changes in synaptic calcium concentration ([Ca2+]), which triggers downstream events involving CaMKII and pCREB (not shown), facilitating the induction of LTP, which promotes dendritic spine enlargement. Alternatively, activation of NR2B containing NMDAR may trigger a low rise in intrasynaptic calcium, which is favored by oAβ interactions with synapses (away from dotted line pathway), leading to calcineurin (CaN) activation; oAβ-dependent active caspase 3 can also activate CaN. Activated CaN dephosphorylates GluR subunits of AMPARs promoting internalization of AMPARs from the surface of synapses leading to LTD, which leads to dendritic spine shrinkage. Furthermore, active CaN dephosphorylates cofilin rendering it active to depolymerize dendritic spine actin, which leads to dendritic spine collapse and synapse loss.