Fig. 4

SorLA localization within a neuron and its signaling in AD. SorLA predominantly localizes in neural soma and dendrites, either in sorting vesicles or at the plasma membrane. Box A) The presence of extracellular BDNF in human brain mediates expression of SORL1, which increases SORLA protein levels attenuating the production and secretion of Aβ. Box B) A scheme of how SorLA regulates EphA4 signaling. Under physiological conditions (left panel), EphA4 binds its juxtapositioned ligand EphA1 which triggers clustering of EphA4 receptors, and their subsequent phosphorylation. EphA4 activation triggers disassembly and retraction of F-actin filaments causing growth cone collapse crucial e.g. for dendritic spine pruning. AD patients (right panel) show increased levels of EphA4 in close proximity to Aβ plaques. Moreover, EphA4 binds Aβ oligomers which results in increased AphA4 activation and abnormal actin filaments retraction causing dendritic spine retraction and synaptic loss. SorLA (middle panel) binds EphA4, which prevents EphA4 clustering. Increased SorLA levels thus diminish the EphA4 activation, which lowers the responsiveness of the neurons to growth cone retraction even in presence of AβO, thus protecting the neurons against synaptotoxicity. Box C) SorLA binds and traffics TrkB receptor towards the synapse where they remain as a receptor complex. Upon BDNF release and subsequent activation of TrkB, SorLA further drives TrkB internalization, which is a critical step for the subsequent BDNF-dependent neurotrophic response and synaptic plasticity