P011 - THE MODE OF SYNERGISTIC SUPPRESSION ON LARGE CONDUCTANCE CALCIUM-ACTIVATED POTASSIUM CHANNEL BY AMYLOID BETA OLIGOMER AND AMYLOID PRECURSOR PROTEIN (ID 281)
Abstract
Aims
We have previously reported that intracellular amyloid β (Aβ) and amyloid precursor protein (APP) cooperatively suppresses the large-conductance calcium-dependent potassium (BK) channel in cortical pyramidal cells from wild type (WT) mice and triple transgenic AD model (3xTg) mice, and activity-dependent expression of the scaffold protein Homer1a reverses this suppression of BK channel. These findings suggest that Long homer, the splicing variant of Homer1a, is the key molecule, given that it forms 4-mer, can bind BK channel and APP which binds Aβ or APP itself for dimerization. This study further investigated the mode of BK channel blockade synergistically mediated by Aβ and APP.
Methods
Whole cell recordings were performed from the pyramidal neurons in frontal neocortical slices of WT or 3xTg mice. Spike properties were recorded under the intracellular injection of recombinant Aβ1-42, full length APP, Bri2 or various antibodies against APP or Aβ through patch pipette.
Results
BK channel suppression still occur even both in intracellularly APP-injected WT neurons in the presence of 11A1 (Aβ oligomer antibody), and in 3xTg neurons in the presence of Bri2, which disrupt the link between Aβ and APP and the processing of APP to Aβ. In Aβ1-42-injected WT neurons, BK channel suppression failed to be reversed by antibodies against APP.
Conclusions
Considering that the APP C-terminus domain is known to bind to the Homer EVH domain, these observations suggest that long Homer and BK channel, together with APP and Aβ oligomer, may form a molecular complex that underlies synergistic BK channel suppression by APP and Aβ oligomer.
