Fig. 8

SorCS3 localization and AD-related signaling. SorCS3 predominantly displays somatodendritic localization, especially at the plasma membrane where it binds its ligands. It is also found in axons but at minor extent. Box A) SorCS3 is a downstream effector of transcription factor Tbr1, which restricts dendritic projections to their synaptic targets during development (left panel). Moreover, SorCS3 transcription is inducible upon various external stimuli such as LTP, seizures or fear conditioning (right panel). Box B) SorCS3 signaling is involved in amoyloidogenic pathway. SorCS3 overexpression (OE) reduces γ-secretase activity and APP processing resulting in lower production and secretion of Aβ. SorCS3 gain of function is thus neuroprotective against accumulation of Aβ oligomers. In contrast, SorCS3 downregulation (KD) results in an enhanced γ-secretase activity and thus larger formation and secretion of Aβ into the extracellular space. Thus, SorCS3 loss of function is neurotoxic as it promotes the amyloidogenic pathway. However, molecular mechanisms behind these observations are unknown. Box C) SorCS3 can signal upon its ligands’ binding already as a proform. Both SorCS3 isoforms bind proNGF and NGF, however the functional consequences remain unknown. SorCS3 can bind TrkB, by which it blunts BDNF-mediated TrkB activation. It is believed that this signaling axis is important for energy metabolism balance. Box D) SorCS3 signaling at the synapse is critical for memory formation and consolidation of excitatory neurons. SorCS3 resides at the postsynaptic side of excitatory neurons where it interacts with PSD95 and probably with PICK1 (the interaction was shown only in the HEK293 cells), which was suggested to mediate the endocytosis and sorting of AMPA receptors, a critical step for GluR- and NMDAR-dependent long-term depression (LTD), spatial learning and fear extinction memory. Notably, Sorcs3 expression is upregulated in engram neurons during memory formation