Hartmann, Stephanie, Zheng, Fang, Kyncl, Michele Constanze, Karch, Sandra, Voelkl, Kerstin, Zott, Benedikt, D'Avanzo, Carla, Lomoio, Selene, Tesco, Giuseppina, Kim, Doo Yeon, Alzheimer, Christian and Huth, Tobias (2018) Beta secretase BACE1 promotes surface expression and function of Kv3.4 potassium channels in hippocampal mossy fiber synapses. Journal of Neuroscience. ISSN 0270-6474

Abstract

In the brain, expression of BACE1 is high during development and declines subsequently. One remarkable exception is the hippocampus, in parts of which BACE1 levels remain elevated into adulthood. The sites of elevated BACE1 in mature hippocampus show a striking overlap with those of the voltage-gated K+ channel 3.4 (Kv3.4), which has also been linked to AD. This presynaptically located K+ channel gives rise to fast activating and inactivating currents that serve to repolarize action potentials that invade the terminals, thereby shaping the kinetics of transmitter release. In view of the prominent parallel enrichment of BACE1 and Kv3.4 in the hippocampus, we investigated whether BACE1 plays a role in Kv3.4 expression and function. Our main findings were:
1) BACE1 and Kv3.4 strictly co-localize in the mossy fiber tract of the hippocampus.
2) Kv3.4-dependent synaptic transmission is altered in BACE1 knockout mice.
3) Hippocampal cell surface levels and synaptic levels (Figure 1) of Kv3.4 are reduced in BACE1 knockout mice.
4) In a cell line, co-expressed BACE1 drastically increases Kv3.4 channel density at the plasma membrane when proteolytically active and, most importantly, also when pharmacologically rendered inactive.
5) BACE1 was immunoprecipitated (IP) with Kv3.4 and vice versa in co-IP experiments in the expression system.

The last two points argue in favor of a non-proteolytic interaction between BACE1 and Kv3.4 as already demonstrated for other K+ channels (Agsten et al., 2015; Hessler et al., 2015). We therefore hypothesized that pharmacological inhibition of the enzymatic activity of BACE1 should not affect its interaction with Kv3.4. This hypothesis, however, was based on over- expression experiments in cell lines. To substantiate the notion that BACE1 interacts with Kv3.4 in a non-enzymatic manner, we planned to investigate synaptic Kv3.4 protein level in C57BL/6 mice which were either fed with BACE1 inhibitor NB-360 containing food pellets or with control pellets for four weeks

Item Type:	Article
Date Deposited:	11 Apr 2018 00:45
Last Modified:	11 Apr 2018 00:45
URI:	https://oak.novartis.com/id/eprint/35306