Amyloid-β Protein Precursor Regulates Depolarization-Induced Calcium-Mediated Synaptic Signaling in Brain Slices.

Background: Coordinated calcium influx upon neuronal depolarization activates pathways that phosphorylate CaMKII, ERKs, and the transcription factor CREB and, therefore, expression of pro-survival and neuroprotective genes. Recent evidence indicates that amyloid-beta protein precursor (A beta PP) is trafficked to synapses and promotes their formation. At the synapse, A beta PP interacts with synaptic proteins involved in vesicle exocytosis and affects calcium channel function. Objective: Herein, we examined the role of A beta PP in depolarization-induced calcium-mediated signaling using acute cerebral slices from wild-type C57bl/6 mice and A beta PP-/- C57bl/6 mice. Methods: Depolarization of acute cerebral slices from wild-type C57bl/6 and A beta PP-/- C57bl/6 mice was used to induce synaptic signaling. Protein levels were examined by western blot and calcium dynamics were assessed using primary neuronal cultures. Results: In the absence of A beta PP, decreased pCaMKII and pERKs levels were observed. This decrease was sensitive to the inhibition of N- and P/Q-typeVoltage Gated Calcium Channels (N- and P/Q-VGCCs) by omega-conotoxin GVIA and omega-conotoxin MVIIC, respectively, but not to inhibition of L-type VGCCs by nifedipine. However, the absence of A beta PP did not result in a statistically significant decrease of pCREB, which is a known substrate of pERKs. Finally, using calcium imaging, we found that down regulation of A beta PP in cortical neurons results in a decreased response to depolarization and altered kinetics of calcium response. Conclusion: A beta PP regulates synaptic activity-mediated neuronal signaling by affecting N- and P/Q-VGCCs.