Fig. 6.

Effect of ApoE isoforms on ApoE receptor signaling at the synapse. Apoer2 induces NMDAR tyrosine phosphorylation by activating SFKs in response to Reelin in the postsynaptic neuron (8, 10, 16). Astrocyte-derived ApoE3 (green ovals) or ApoE4 (gray ovals) bind to Apoer2 and are constitutively but slowly internalized. Apoer2 undergoes accelerated endocytosis in response to Reelin signaling (Fig. 1) (25). ApoE4 sequesters Apoer2 in intracellular compartments thereby reducing the ability of the postsynaptic neuron to phosphorylate (activate) NMDA receptors in response to Reelin (shown on the right), whereas ApoE2 or ApoE3 efficiently recycle back to the cell surface and thus deplete surface Apoer2 levels to a lesser extent (illustrated on the left for ApoE3). Aβ oligomers interfere with NMDAR tyrosine phosphorylation by activating tyrosine phosphatases (13, 24).