BACE1 regulates voltage-gated sodium channels and neuronal activity

Kim, Doo Yeon; Carey, Bryce W.; Wang, Haibin; Ingano, Laura; Binshtok, Alexander M.; Wertz, Mary H.; Pettingell, Warren H.; He, Ping; Lee, Virginia M.‐Y.; Woolf, Clifford J.; Kovacs, Dora M.

doi:10.1038/ncb1602

Cited by 283 publications

(339 citation statements)

References 46 publications

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“…57 In BACE1-transgenic mice and in temporal cortex of AD patients, increased BACE1 levels were found to be associated with enhanced b2 cleavage. 58 Moreover, that study revealed that the generated b2 intracellular domain acted as transcriptional activator for its Na v 1.1 a-subunit and increased Na v 1.1 protein, which was, however, retained intracellularly. Consistent with the findings in BACE1-over-expressing mice, Corbett et al…”

Section: Bace1 and Neuronal Na V Channelsmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Bace1 and Neuronal Na V Channelsmentioning

confidence: 99%

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

et al. 2016

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“…In addition to APP, a number of other putative BACE1 substrates have been identified, including neuregulin (NRG1; Lindholm et al, 2002;Wong et al, 2005), voltage-gated sodium channel (VGSC; Na v ) subunits Kim et al, 2007), lipoproteinlike receptor related protein (LRP; von Arnim et al, 2005), amyloid precursor-like proteins (APLP; Li and Sudhof, 2004;Pastorino et al, 2004), P-selectin glycoprotein ligand 1 (PSGL-1; Lichtenthaler et al, 2003) and beta-galactoside alpha 2,6-sialyltransferase (ST6Gal I; Kitazume et al, 2005). Importantly, many of these substrates may play a role in neuronal function (NRG1, VGSCβ subunits) and the cellular response to stress and/or injury, such as recovery from excitotoxicity (Aβ; Kamenetz et al, 2003), Aβ clearance (LRP; Hyman et al, 2000), synapse formation (APP, APLP1, APLP2; Herms et al, 2004;Wang et al, 2005) and immune functions (PSGL-1, ST6Gal I; Lichtenthaler et al, 2003;Kitazume et al, 2005).…”

Section: Cellular Changes Associated With Vascular Diseases Can Elevamentioning

confidence: 99%

Linking vascular disorders and Alzheimer's disease: Potential involvement of BACE1

Cole¹,

Vassar²

2009

Neurobiology of Aging

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The etiology of Alzheimer's disease (AD) remains unknown. However, specific risk factors have been identified, and aging is the strongest AD risk factor. The majority of cardiovascular events occur in older people and a close relationship between vascular disorders and AD exists. Amyloid plaques, composed of the beta amyloid peptide (Aβ), are hallmark lesions in AD and evidence indicates that Aβ plays a central role in AD pathophysiology. The BACE1 enzyme is essential for Aβ generation, and BACE1 levels are elevated in AD brain. The cause(s) of this BACE1 elevation remains undetermined. Here we review the potential contribution of vascular disease to AD pathogenesis. We examine the putative vasoactive properties of Aβ and how the cellular changes associated with vascular disease may elevate BACE1 levels. Despite increasing evidence, the exact role(s) vascular disorders play in AD remains to be determined. However, given that vascular diseases can be addressed by lifestyle and pharmacologic interventions, the potential benefits of these therapies in delaying the clinical appearance and progression of AD may warrant investigation.

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“…However, characterization of BACE1 substrates other than APP (including the voltage-gated sodium channel Na(v)1 ␤2-subunit and neuregulin 1) pointed out the role of BACE1 in neuronal functions (24,25). Studies analyzing BACE1 knockout mice indeed highlighted dysfunctions in synaptic transmission and plasticity (26 -28).…”

mentioning

confidence: 99%

Processing of the Synaptic Cell Adhesion Molecule Neurexin-3β by Alzheimer Disease α- and γ-Secretases

Bot

Schweizer

Halima³

et al. 2011

Journal of Biological Chemistry

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Neurexins (NRXNs) are synaptic cell adhesion molecules having essential roles in the assembly and maturation of synapses into fully functional units. Immunocytochemical and electrophysiological studies have shown that specific binding across the synaptic cleft of the ectodomains of presynaptic NRXNs and postsynaptic neuroligins have the potential to bidirectionally coordinate and trigger synapse formation. Moreover, in vivo studies as well as genome-wide association studies pointed out implication of NRXNs in the pathogenesis of cognitive disorders including autism spectrum disorders and different types of addictions including opioid and alcohol dependences, suggesting an important role in synaptic function. Despite extensive investigations, the mechanisms by which NRXNs modulate the properties of synapses remain largely unknown. We report here that ␣-and ␥-secretases can sequentially process NRXN3␤, leading to the formation of two final products, an ϳ80-kDa N-terminal extracellular domain of Neurexin-3␤ (sNRXN3␤) and an ϳ12-kDa C-terminal intracellular NRXN3␤ domain (NRXN3␤-ICD), both of them being potentially implicated in the regulation of NRXNs and neuroligins functions at the synapses or in yet unidentified signal transduction pathways. We further report that this processing is altered by several PS1 mutations in the catalytic subunit of the ␥-secretase that cause early-onset familial Alzheimer disease.

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BACE1 regulates voltage-gated sodium channels and neuronal activity

Cited by 283 publications

References 46 publications

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

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

Linking vascular disorders and Alzheimer's disease: Potential involvement of BACE1

Processing of the Synaptic Cell Adhesion Molecule Neurexin-3β by Alzheimer Disease α- and γ-Secretases

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