Calsenilin is a presenilin-binding protein, increasing γ-cleavage of the Alzheimer amyloid protein precursor, thereby elevating the amyloid β protein (Aβ)¹. Calsenilin is also a Kv4 channel interacting protein (KChIP3), responsible for protein trafficking of Kv4 channels². We have previously shown that Aβ increases expression of ‘A’-type K+ channel currents in rat cerebellar granule neurons³. This increase is due to the upregulation of the Kv4.2 subunit in particular⁴. Here we investigate the effect of soluble Aβ1-40 on the Kv4.2 subunit and the importance of its association with KChIP3. Dissociated cultures of cerebellar granule neurones (CGN) were prepared from 6-8 day old rats. Whole-cell patch clamp measurements of K+ channel currents were carried out using quasi-physiological intra- and extracellular solutions³. Stock Aβ was solubilised in DMSO before dilution in culture media to a concentration of 10nM and applied to cultures for 24 hours. Immunopharmacological techniques were employed by adding antibodies into the intracellular pipette solution. This would preferentially block the protein of interest enabling functional properties to be investigated. Protein expression for KChIP3 and Kv4.2 in the presence of Aβ (10nM, 24hours) were assayed using western blotting. The importance of endogenous Aβ was considered by application of the γ-secretase inhibitor, γ-I (10μM, 24 hours) which blocks the production of Aβ1-40 at the presenilin complex. Statistical differences were assessed using repeated measures ANOVA with Tukey’s posthoc test or unpaired Student’s t-test as appropriate. Soluble rat recombinant Aβ1-40 caused a significant increase in peak K+ current density/voltage (I-V) relationships, similar to previously reported data⁵. This increase was significantly blocked by 35.38±0.9 % in the presence of the intracellular Kv4.2 antibody (n=10 control Kv1.4 antibody, 10 Kv4.2 antibody p<0.001). At a test potential of 50mV, current decreased from 0.86±0.07 nA/pF to 0.56±0.05 nA/pF. In another set of similar experiments the increase in peak K+ current of Aβ1-40 treated cells were significantly blocked by 19.5±0.93%, in the presence of the intracellular KChIP3 antibody (n=11 control KChIP2 antibody, 10 KChIP3 antibody, p<0.05). Western blotting revealed a 30.0±0.1% increase in KChIP3 protein levels after Aβ1-40 treatment (n=4 control, Aβ treated, p<0.05). When endogenous Aβ1-40 levels were inhibited by γ-I, protein expression of KChIP3 significantly increased by 56.0±0.1% (n=3 control, γ-I treated cells, p<0.05). These data suggest the increase in ‘A’-type K+ current in the presence of Aβ1-40 is due to involvement of the Kv4.2 subunits by augmenting its association with KChIP3.