Identification of a Novel Aspartic Protease (Asp 2) as β-Secretase

Hussain, Ishrut; Powell, David J.; Howlett, David; Tew, David G.; Meek, Thomas D.; Chapman, C.G.; Gloger, Israel; Murphy, Kay E.; Southan, Christopher; Ryan, Dominic M.; Smith, Trudi S.; Simmons, David L.; Walsh, Frank S.; Dingwall, Colin; Christie, Gary

doi:10.1006/mcne.1999.0811

Cited by 1,027 publications

(654 citation statements)

References 22 publications

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“…In 1999, BACE1 (also: b-secretase 1 or memapsin 2) was identified as a b-site APP-cleaving enzyme, [7][8][9][10][11] and, 2 years later, confirmed as the major b-secretase in vivo. 12 BACE1 initiates the amyloidogenic pathway of APP processing.…”

Section: Role Of Bace1 In Admentioning

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: Role Of Bace1 In Admentioning

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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“…This enzymatic action leads to the release of a large soluble extracellular amino terminal fragment of APP (sAPP α ) and of a non-amyloidogenic 83-amino acid C-terminal fragment (C83). Conversely, in an amyloidogenic pathway, APP could be alternatively cleaved at a position located 99 amino acids from the C-terminus by a β -secretase, an aspartyl protease known as BACE1 ( β -site APP-cleaving enzyme) (Hussain et al , 1999 ). Cleavage by β -secretase releases a slightly shorter soluble APP peptide (sAPP β ) in the extracellular space and leaves a 99-amino acids C-terminal fragment (C99) within the membrane.…”

Section: App Metabolism and A β Formationmentioning

confidence: 99%

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

Bordji

Becerril-Ortega

2011

Revneuro

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A direct relationship has been established between synaptic activity and amyloid-β secretion. Dysregulation of neuronal calcium homeostasis was shown to increase production of amyloid-β , contributing to the initiation of Alzheimer ' s disease. Among the different routes of Ca 2 + entry, N -methyld -aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are especially involved in this process because of their ability to gate high levels of Ca 2 + infl ux. These receptors have been extensively studied for their crucial roles in synaptic plasticity that underlies learning and memory but also in neurotoxicity occurring during acute brain injuries and neurodegenerative diseases. For one decade, several studies provided evidence that NMDA receptor activation could have distinct consequences on neuronal fate, depending on their location. Synaptic NMDA receptor activation is neuroprotective, whereas extrasynaptic NMDA receptors trigger neuronal death and/or neurodegenerative processes. Recent data suggest that chronic activation of extrasynaptic NMDA receptors leads to a sustained neuronal amyloid-β release and could be involved in the pathogenesis of Alzheimer ' s disease. Thus, as for other neurological diseases, therapeutic targeting of extrasynaptic NMDA receptors could be a promising strategy. Following this concept, memantine, unlike other NMDA receptor antagonists was shown, to preferentially target the extrasynaptic NMDA receptor signaling pathways, while relatively sparing normal synaptic activity. This molecular mechanism could therefore explain why memantine is, to date, the only clinically approved NMDA receptor antagonist for the treatment of dementia.

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“…Nowadays, β-secretase is considered the initial and rate-limiting enzyme during this process. β-site APP cleavage enzyme (BACE), a type I integral membrane aspartic protease, was identified as the main β-secretase [3][4][5][6][7]. As formation of senile plaques could not be detected in BACE-deficient mice [8,9], BACE has attracted major attentions in AD research during recent years.…”

Section: Introductionmentioning

confidence: 99%

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

et al. 2007

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Amyloid-β (Aβ) peptide, the primary constituent of senile plaques in Alzheimer's disease (AD), is generated by β-secretase-and γ-secretase-mediated sequential proteolysis of the amyloid precursor protein (APP). The aspartic protease, β -site APP cleavage enzyme (BACE), has been identified as the main β-secretase in brain but the regulation of its activity is largely unclear. Here, we demonstrate that both BACE activity and subsequent Aβ production are enhanced after stimulation of receptor tyrosine kinases (RTKs), such as the receptors for epidermal growth factor (EGF) and nerve growth factor (NGF), in cultured cells as well as in mouse hippocampus. Furthermore, stimulation of RTKs also induces BACE internalization into endosomes and Golgi apparatus. This enhancement of BACE activity and Aβ production upon RTK activation could be specifically inhibited by Src family kinase inhibitors and by depletion of endogenous c-Src with RNAi, and could be mimicked by over-expressed c-Src. Moreover, blockage of BACE internalization by a dominant negative form of Rab5 also abolished the enhancement of BACE activity and Aβ production, indicating the requirement of BACE internalization for the enhanced activity. Taken together, our study presents evidence that BACE activity and Aβ production are under the regulation of RTKs and this is achieved via RTK-stimulated BACE internalization, and suggests that an aberration of such regulation might contribute to pathogenic Aβ production.

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Identification of a Novel Aspartic Protease (Asp 2) as β-Secretase

Cited by 1,027 publications

References 22 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

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

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