Fig. 6

Vesicular acidification by NHE6 impacts ApoE4 stability. The APOE receptor 2 (APOER2) binds the different ApoE isoforms, which are subsequently internalized into endosomes. Passing through the cellular transport axis, endosomes start to acidify through a continuous electrogenic proton influx, pumped into to lumen by V-ATPases. To ascertain that proton accretion is bound within limits, channels can exchange these protons for 2 Cl⁻ or Na⁺, performed by i.a. the Na⁺/H⁺ exchanger NHE6. Under healthy conditions, the acidification enables the APOER2 to be dislodged from APOE, which then relocates to the cell surface again to contribute in N-methyl-D-aspartate receptor (NMDAR) activation. Fluctuations of pH are not only important for a proper receptor recycling, but also for a correct folding of ApoE. The isoelectric point of ApoE4 is higher as the ones of ApoE2 and E3, making its isoelectric point to be already reached in endosomes in contrast to the other variants. Hence, ApoE4 will adapt a molten globule state in sorting endosomes-lysosomes, which not only promotes APOER2 clustering (hindering recycling to the plasma membrane) but also displays a high affinity for phospholipids. These are most likely oxidatively damaged, impacting the mechanical characteristics of the membrane and, as such, their capacity to withstand disruptions e.g. induced by Aβ. The therapeutic potential of targeting this pH-linked instability of ApoE4 has been positively assessed, reducing the levels of the Na⁺/H⁺ exchanger NHE6 and using sodium channel blocking amiloride analogs. Aside from ApoE isoforms, the APOER2 interacts with the extracellular matrix serine protease – Reelin – in a competitive fashion. Upon activation by Reelin, a signaling cascade is induced which abrogates tau hyperphosphorylation and promotes the influx of Ca²⁺ through the NMDAR