The role of intracellular trafficking and the VPS10d receptors in Alzheimer's disease

Abstract

In Alzheimer's disease, the key pathological culprit is the amyloid-β protein, which is generated through β- and γ-secretase cleavage of the amyloid-β precursor protein (APP). Both the secretases and amyloid-β precursor protein are transmembrane proteins that are sorted via the trans-Golgi network and the endosome through multiple membranous compartments of the cell. The coat complex clathrin controls the sorting from the cell surface and the trans-Golgi network to the endosome. Instead, the retromer controls the reverse transport from the endosome to the trans-Golgi network. The retromer contains two subprotein complexes: the cargo-selective subcomplex consisting of VPS35, VPS29 and VPS26 and the membrane deformation subcomplex consisting of Vps5p, Vps17p, SNX 1/2 and possibly SNX 5/6 or SNX 32 in mammals. Cargo molecules of the retromer include the VPS10 receptor proteins SORL1, SORT1, SORCS1, SORCS2 and SORCS3. There is increasing evidence through cell biology and animal and genetic studies that components of the retromer and the VPS10d receptor family play a role in the etiology of Alzheimer's disease. This article reviews and summarizes this current evidence.

Figure 1. APP sorting in Alzheimer's disease (simplified model to aid clarity)

APP and BACE are sorted through the TGN–cell surface–endosome network. The coat complex, clathrin, controls the transport from both the cell surface and the TGN to the endosome (solid black arrows). The retromer instead controls the reverse transport from the endosome to the TGN (dashed arrow). APP and BACE interact within the endosomal system, representing the first step of the amyloidogenic pathway. SORL1 modulates the sorting of APP. When SORL1 is absent, APP holoprotein is switched away from the recycling pathway through the retromer but is instead directed into the β-secretase cleavage pathway (white arrow), thereby increasing APP's Aβ production. Subsequently, APP enters the γ-secretase cleavage pathway to generate Aβ. BACE: β-secretase; TGN: Trans-Golgi network.

Figure 2. The distinct cargo-selective and membrane deformation subcomplexes that together form the mammalian SNX-BAR-retromer

The mammalian genome contains two VPS26 genes.