β-Secretase BACE1 Promotes Surface Expression and Function of Kv3.4 at Hippocampal Mossy Fiber Synapses

Abstract

The β-secretase β-site APP-cleaving enzyme 1 (BACE1) is deemed a major culprit in Alzheimer's disease, but accumulating evidence indicates that there is more to the enzyme than driving the amyloidogenic processing of the amyloid precursor protein. For example, BACE1 has emerged as an important regulator of neuronal activity through proteolytic and, most unexpectedly, also through nonproteolytic interactions with several ion channels. Here, we identify and characterize the voltage-gated K channel 3.4 (Kv3.4) as a new and functionally relevant interaction partner of BACE1. Kv3.4 gives rise to A-type current with fast activating and inactivating kinetics and serves to repolarize the presynaptic action potential. We found that BACE1 and Kv3.4 are highly enriched and remarkably colocalized in hippocampal mossy fibers (MFs). In BACE1 mice of either sex, Kv3.4 surface expression was significantly reduced in the hippocampus and, in synaptic fractions thereof, Kv3.4 was specifically diminished, whereas protein levels of other presynaptic K channels such as K1.1 and K2.3 remained unchanged. The apparent loss of presynaptic Kv3.4 affected the strength of excitatory transmission at the MF-CA3 synapse in hippocampal slices of BACE1 mice when probed with the Kv3 channel blocker BDS-I. The effect of BACE1 on Kv3.4 expression and function should be bidirectional, as predicted from a heterologous expression system, in which BACE1 cotransfection produced a concomitant upregulation of Kv3.4 surface level and current based on a physical interaction between the two proteins. Our data show that, by targeting Kv3.4 to presynaptic sites, BACE1 endows the terminal with a powerful means to regulate the strength of transmitter release. The β-secretase β-site APP-cleaving enzyme 1 (BACE1) is infamous for its crucial role in the pathogenesis of Alzheimer's disease, but its physiological functions in the intact nervous system are only gradually being unveiled. Here, we extend previous work implicating BACE1 in the expression and function of voltage-gated Na and K channels. Specifically, we characterize voltage-gated K channel 3.4 (Kv3.4), a presynaptic K channel required for action potential repolarization, as a novel interaction partner of BACE1 at the mossy fiber (MF)-CA3 synapse of the hippocampus. BACE1 promotes surface expression of Kv3.4 at MF terminals, most likely by physically associating with the channel protein in a nonenzymatic fashion. We advance the BACE1-Kv3.4 interaction as a mechanism to strengthen the temporal control over transmitter release from MF terminals.

A New Fluorogenic Small-Molecule Labeling Tool for Surface Diffusion Analysis and Advanced Fluorescence Imaging of β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 Based on Silicone Rhodamine: SiR-BACE1

“…[69][70][71][72][73] We have previously revealed the interaction of BACE1 with the voltage-gated sodium channel NaV1.2, voltage-gated potassium channel KV3.4, and potassium channels of the KCNQ family (KCNQ1-3), for which BACE1 acts as a non-proteolytic accessory subunit. 22,[74][75][76][77] Both NaV1.2 and KCNQ2/3 are anchored to the actin cytoskeleton at the axon initial segment by interaction with ankyrin-G. 78 A similar anchoring to actin has been described for KCNQ1 via the protein kinase A anchoring protein (AKAP) yotiao. 50,79 It is therefore conceivable that the restricted motility of BACE1 results, at least in part, from its physical association with anchored membrane proteins.…”

β-Secretase BACE1 Is Required for Normal Cochlear Function

“…of gray (Fig. 8A) (Shimshek et al, 2016;Hartmann et al, 2018). Western blot analysis of amyloid precursor protein (APP) and contactin-2 (CNTN2 (Gautam et al, 2014), two known BACE1 substrates, demonstrated a significant increase of the respective, unprocessed full-length protein (Fig.…”

The meaning of blood and cerebrospinal fluid biomarkers in early diagnosis of Alzheimer's disease

“…20 This pathway is widely regarded as the primary pathogenic mechanism in Alzheimer's disease. 24 According to studies, elevated levels of BACE1 in the CSF are noticeable in the later stages of sporadic Alzheimer's disease. This is due to the association of the BACE1 level with the level of amyloidogenesis and the intensity of axon degradation.…”