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

Abstract

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-β protein precursor (AβPP) is trafficked to synapses and promotes their formation. At the synapse, AβPP interacts with synaptic proteins involved in vesicle exocytosis and affects calcium channel function. Herein, we examined the role of AβPP in depolarization-induced calcium-mediated signaling using acute cerebral slices from wild-type C57bl/6 mice and AβPP-/- C57bl/6 mice. Depolarization of acute cerebral slices from wild-type C57bl/6 and AβPP-/- 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. In the absence of AβPP, decreased pCaMKII and pERKs levels were observed. This decrease was sensitive to the inhibition of N- and P/Q-type Voltage Gated Calcium Channels (N- and P/Q-VGCCs) by ω-conotoxin GVIA and ω-conotoxin MVIIC, respectively, but not to inhibition of L-type VGCCs by nifedipine. However, the absence of AβPP 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 AβPP in cortical neurons results in a decreased response to depolarization and altered kinetics of calcium response. AβPP regulates synaptic activity-mediated neuronal signaling by affecting N- and P/Q-VGCCs.