Fig. 2

The ApoER2-Dab1 pathway and its proposed role in pTau-associated neurodegeneration in sAD. The ApoER2-Dab1 pathway suppresses Tau phosphorylation as part of a four-arm pathway that stabilizes actin, microtubules, and synapses, and delivers essential lipid cargo via receptor-mediated lipoprotein internalization. Nine core components of the ApoER2-Dab1 pathway that are a focus of the current paper are illustrated in the figure and described below. Under physiological conditions, binding of ligands (ApoE [1]), Reelin [2]), ApoJ [3]) to ApoER2 [4] triggers recruitment of Dab1 [5] and P85α [6] to lipid rafts, formation of ApoER2-Dab1-P85α signaling complexes, and phosphorylation, activation, and degradation of Dab1. Ensuing activation of the Dab1-P85α/PI3K cascade evokes phosphorylation of LIMK1 [7] to stabilize the actin cytoskeleton, and inhibition of GSK3β, which in turn inhibits phosphorylation of Tau [8] and PSD95 [9] to stabilize microtubules and postsynaptic receptor complexes, respectively. Disruption of this pathway at the level of ApoER2 (gray oval near ApoER2) is proposed to destabilize actin, microtubules, and synapses, to disrupt lipoprotein internalization, and to induce the co-accumulation of multiple ApoER2-Dab1 pathway components in sAD