Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

Abstract

b-site APP-cleaving enzyme 1 (BACE1) has become infamous for its pivotal role in the pathogenesis of Alzheimer's disease (AD). Consequently, BACE1 represents a prime target in drug development. Despite its detrimental involvement in AD, it should be quite obvious that BACE1 is not primarily present in the brain to drive mental decline. In fact, additional functions have been identified. In this review, we focus on the regulation of ion channels, specifically voltage-gated sodium and KCNQ potassium channels, by BACE1. These studies provide evidence for a highly unexpected feature in the functional repertoire of BACE1. Although capable of cleaving accessory channel subunits, BACE1 exerts many of its physiologically significant effects through direct, non-enzymatic interactions with main channel subunits. We discuss how the underlying mechanisms can be conceived and develop scenarios how the regulation of ion conductances by BACE1 might shape electric activity in the intact and diseased brain and heart.

Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1

“…Evidence has been accumulating that multiple functional abnormalities in J20 mice, and possibly also some of those observed in humans with AD, are caused by impairments of inhibitory interneurons, which-in turn-result, at least in part, from the depletion of specific voltage-gated sodium channels [54,60,124]. Although the mechanisms underlying this depletion remain to be determined, BACE1-mediated cleavage of Na V β2 has been implicated in the hypofunction of AD-relevant sodium channels in APP transgenic mice [125,126]. We examined sodium channel levels in the parietal cortex because we previously detected sodium channel depletions only in this brain region but not in the hippocampus [54].…”

BACE1 Function and Inhibition: Implications of Intervention in the Amyloid Pathway of Alzheimer’s Disease Pathology

“…Further implicating a specific role of BACE1 in the CNS, the processing of Navβ2 [ 79 , 92 ] results in reduced secretion of the Navβ2 to the plasma membrane and reduced sodium current densities that result in hyperexcitability to an extent consistent with seizures observed in BACE1 knockout animals [ 93 ]. Additionally, BACE1 was found to interact non-catalytically with the main α subunits of sodium and potassium channels and may serve as the β subunit [ 93 , 94 , 95 ].…”

“…Further implicating a specific role of BACE1 in the CNS, the processing of Navβ2 [ 79 , 92 ] results in reduced secretion of the Navβ2 to the plasma membrane and reduced sodium current densities that result in hyperexcitability to an extent consistent with seizures observed in BACE1 knockout animals [ 93 ]. Additionally, BACE1 was found to interact non-catalytically with the main α subunits of sodium and potassium channels and may serve as the β subunit [ 93 , 94 , 95 ]. Thus, interpretation of BACE1 gene depletion would impact both roles of BACE1 in cellular excitability, whereas inhibition of BACE1 would reduce processing of β subunits, with less expectation to impact BACE1 participation as a β subunit where its catalytic activity has been demonstrated to be dispensable [ 93 , 95 ].…”

“…Additionally, BACE1 was found to interact non-catalytically with the main α subunits of sodium and potassium channels and may serve as the β subunit [ 93 , 94 , 95 ]. Thus, interpretation of BACE1 gene depletion would impact both roles of BACE1 in cellular excitability, whereas inhibition of BACE1 would reduce processing of β subunits, with less expectation to impact BACE1 participation as a β subunit where its catalytic activity has been demonstrated to be dispensable [ 93 , 95 ].…”

“…The BACE1 deficiency studies ( Table 3 and reviews referenced) span from embryonic development throughout adult life and therefore may not be suitable for comparison to studies that evaluate the toxicity or safety of a treatment regimen of a particular compound [ 169 ]. For example, BACE1 participation as a β subunit in sodium and potassium channels would be impacted by BACE1 depletion but may not be expected to be impacted by inhibition of BACE1 proteolytic activity ([ 93 ]; discussed in section above). Additionally, differences in the extent of pharmacologic inhibition may explain to some extent the discord between KO and pharmacologic inhibition studies in functional CNS outcomes [ 14 , 29 ].…”