RAGE and LRP1 modulation in TgCRND8 mice under condition of B-vitamin deficiency

Abstract

retromer complex. Methods: We have generated SORLA variants lacking binding sites for GGA, PACS1 and the retromer subunit VPS35, and we have explored the consequence of disrupted adaptor interaction for intracellular transport of the receptor and for APP processing both in cultured cells and in mouse models in vivo.Results:When tested in cultured cells, expression of SORLA variants lacking the GGA binding site caused faulty recycling of the receptor and of APP from the early endosomes back to the cell surface and an increase in soluble APP alpha and a decrease in Abeta production. Disrupting the PACS1 binding site, on the other hand, resulted in shunt of the receptor and of APP to the plasma membrane and in massive increase in Abeta levels. To confirm the relevance of altered SORLA trafficking for APP processing in vivo, we generated ROSA26 knock-in mouse models expressing receptor variants lacking the binding sites for GGA, PACS1, and VPS35. Multiple transgenic lines expressing SORLA trafficking mutants under control of the endogenous ROSA26 promoter or the CAG promoter were produced. Robust expression of the receptor variants was seen in multiple tissues including the brain. Currently, these mouse lines are studied to explore the consequences of altered transport of SORLA for amyloidogenic processes. Conclusions: Our cell data indicated that aberrant targeting of SORLA to the recycling compartment or the plasma membrane causes faulty APP trafficking and imbalance in non-amyloidogenic and amyloidogenic processing fates. Thus, novel mouse models expressing trafficking mutants of SORLA represent unique tools to further validate the relevance of SORLA and adaptor interaction for amyloidogenic processing and neurodegeneration in vivo.