Figure 11.

Model for Pyk2 action in AD risk. The proposed mechanism for Pyk2 in Aβo-induced AD signaling at the PSD of dendritic spines is illustrated. In the healthy basal state at left, Pyk2 and Fyn activation is limited (black lettering) and Graf1c actively (white lettering) suppresses RhoA signaling to the actin cytoskeleton to maintain synaptic morphology. In AD (right), Aβo binds to PrP^C to engage mGluR5 and activate Fyn kinase (white lettering). Fyn phosphorylates Pyk2 kinase (white lettering, orange P) this leads to Pyk2 activation (white lettering), autophosphorylation (red P) and Pyk2 recruitment to the PSD. Pyk2 physically interacts with Graf1c at the PSD, phosphorylates Graf1c (red P) and inactivates Graf1c GAP activity (black lettering). Loss of Graf1c function allows increased active RhoA GTPase and subsequent ROCK2-dependent actin contractility, to retract dendritic spines and cause synapse loss. Human genetic variants at the Pyk2 locus, which have been shown to increase Pyk2 mRNA expression, enhance this pathway and thereby increase AD risk.