Fig. 5

Functional involvement of Sortilin in AD-related signaling. Sortilin localizes in sorting vesicles and on the plasma membrane (PM) in neuronal somas, dendrites and axons. Box A) Sortilin undergoes ectodomain shedding by ADAM10/17, which produces soluble Sortilin fragments. In humans, C-terminal fragments are found within the Aβ plaques, however, their precise origin and trafficking route is unknown (marked as “?”). Box B) Sortilin binds BACE1 in TGN and facilitates its intracellular trafficking via anterograde and retrograde pathways, the later directed either towards the recycling pathway or for the lysosomal degradation. Box C) Sortilin binds APP at PM; however, its involvement in APP processing is controversial. Left panel—Sortilin binds APP at axonal PM where they undergo internalization. Sortilin either traffics APP for its lysosomal degradation (a.) or engages in amyloidogenic pathway by enhancing APP cleavage by BACE1 (b.), subsequently causing an increased formation and secretion of sAPPβ and Aβ. Sortilin is also a PSEN1/2 substrate. Right panel – Sortilin has a neuroprotective role as it mediates the uptake of soluble APP from the extracellular space (1.) for lysosomal degradation thus decreasing their extracellular concentration. Moreover, Sortilin binds APP in neurites where it drives its preferential cleavage by ADAM10/17 (2.), thus elevating sAPPα levels. Consequently, there is less APP internalized (3.) prior the sequential cleavage by β- and γ-secretases (4.), resulting in decreased production of sAPPβ and Aβ (4.-5.). However, the molecular mechanisms are rather unknown (marked with “?”). Box D) Upon proNGF binding, Sortilin forms a complex with p75^NTR receptor, which mediates pro-apoptotic cell responses (left). The presence of AβO increases Sortilin expression, which likely enhances the formation and activity of Sortilin-p75^NTR complexes. Sortilin-p75.^NTR complex binds and internalizes AβO leading to increased intracellular neurotoxicity, and later cell death (middle). Sortilin can also bind and sequester extracellular ApoE, subsequently facilitating its lysosomal degradation, which has a neuroprotective effect (right). It is not clear if Sortilin sequesters ApoE-Aβ complexes (marked as “?”)