Figure 2.

Scheme depicting how Uch-L1 affects PKA activity, enhances pCREB levels, and improves synaptic plasticity (adapted from Gong et al., 2006). Aβ inhibits adenylate cyclase (AC) and proteasomal degradation of the RIIa subunit (R), resulting in its accumulation and a shift of the equilibrium in the PKA complex toward the inactive tetramer. As a consequence, the transcription factor CREB cannot be phosphorylated and initiates transcription. Uch-L1 re-establishes normal proteasomal activity leading to normal levels of RIIa subunit which in turn phosphorylates CREB, thus rescuing synaptic function.