Fig. 11
Dendritic ApoER2-Dab1 pathway disruption links four pTau-containing lesions. The ApoER2-Dab1 pathway disruption hypothesis can mechanistically and spatially link four pTau-containing lesions (NTs [1], NFTs [2], NPs [3], GVDs [4]). ApoER2-Dab1 disruption is proposed to trigger Tau hyperphosphorylation and thus the presence of ApoER2 in neuronal membranes confers vulnerability to pTau-associated neurodegeneration. In this model, a triggering molecular lesion or competitive inhibition among ligands disrupts ApoER2 binding, leading to extracellular trapping and accumulation of the ApoER2 ligands ApoE, Reelin, and ApoJ in NPs. Impaired ApoER2 signaling disrupts Dab1 degradation leading to localized neuritic Dab1 accumulation. Ensuing disruption of the Dab1-P85α/PI3K-LIMK1 arm destabilizes the actin cytoskeleton and induces pP85αTyr607 and pLIMK1Thr508 accumulation. Impaired Reelin-ApoER2-Dab1-P85α/PI3K signaling activates GSK3β; ensuing hyperphosphorylation of Tau and PSD95 destabilizes microtubules and postsynaptic receptor complexes, and promotes accumulation of pTauSer202/Thr205 and pPSD95Thr19 in NTs, NFTs, NPs and GVDs. Thus, the ApoER2-Dab1 pathway disruption model attributes deficits in memory and cognition in sAD to impaired neuronal lipoprotein internalization and destabilization of actin, microtubules, and synapses. Our observation that multiple ApoER2-Dab1 pathway components accumulate in the immediate vicinity of NFTs, NTs, NPs, and GVDs is consistent with this model