Figure 7

Diagram of potential APOE4 -induced decrease in synapse-related proteins and disruption of NMDAR-mediated signaling, resulting in impaired learning and memory. With APOE4, the levels of key post-synaptic proteins are reduced, including the subunits of NMDAR. NMDAR signaling via activation by phosphorylation of CaMK-II and CREB to increase expression of BDNF is also disrupted by APOE4, compromising synaptic function and impairing learning and memory. Previous work has demonstrated that apoE isoform-specific effects on Aβ clearance and interactions with apoE receptors likely play a role in this process at several levels. Soluble levels of Aβ are lower with apoE3 and inversely correlated with levels of apoE3/Aβ complex [59], suggesting a potential clearance mechanism. LRP mediates Aβ uptake by neurons [101,102], and, in vitro, Aβ clearance is impaired with apoE4 [103], consistent with a greater accumulation of intraneuronal Aβ [104] compared to apoE3. For ApoER2, ligand recycling is impaired with apoE4 compared to apoE3 [46]. Loss of ApoER2 reduces Reelin binding, thus reducing activation of NMDAR via signaling by the Src family kinases [46,105], leading to decreased synaptic function and therefore decreased learning and memory.