Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease

Zhang, Zhentao; Song, Mingke; Liu, Xia; Kang, Seong Su; Duong, Duc M.; Seyfried, Nicholas T.; Cao, Xin; Cheng, Liming; Sun, Yi; Yu, Shan Ping; Jia, Jianping; Levey, Aĺlan I.; Ye, Keqiang

doi:10.1038/ncomms9762

Cited by 223 publications

(242 citation statements)

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“…d-secretase and h-secretase, is just beginning to emerge. 13,14 In healthy brain, non-amyloidogenic and amyloidogenic processing are balanced, with Ab peptides being important effectors in synaptic transmission and plasticity. 15,16 In 2003, Yang et al reported enhanced BACE1-mediated amyloidogenic cleavage in AD.…”

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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“…1B) (20). AEP is a pH-controlled soluble lysosomal cysteine protease that cleaves after asparagine residues.…”

Section: ␦-Secretasementioning

confidence: 99%

“…AEP is a pH-controlled soluble lysosomal cysteine protease that cleaves after asparagine residues. In an elegant series of experiments, Zhang et al (20) showed that AEP, or ␦-secretase, cleaves APP FIGURE 1. The proteolytic processing of APP.…”

Section: ␦-Secretasementioning

confidence: 99%

“…Cleavage of APP before Thr 584 was described previously and referred to as ␦-cleavage, although the protease responsible was not identified (21). The AEP cleavage of APP could be blocked in vitro using buffers in which the pH (pH 7.4) inhibited the catalytic activity of AEP, by mutation of critical residues (Cys 189 and Asn 323 ) within the catalytic domain of AEP, by mutation of the ␦-secretase cleavage sites within APP, or through antibody or peptide inhibition of the enzyme (20). The shorter N-terminal APP fragment, sAPP , produced by AEP cleavage, but not the sAPP or sAPP 374 -585 fragments (Fig.…”

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confidence: 99%

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A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

Andrew

Kellett

Wang

et al. 2016

Journal of Biological Chemistry

150

122

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Proteolysis of the amyloid precursor protein (APP) liberates various fragments including the proposed initiator of Alzheimer disease-associated dysfunctions, amyloid-␤. However, recent evidence suggests that the accepted view of APP proteolysis by the canonical ␣-, ␤-, and ␥-secretases is simplistic, with the discovery of a number of novel APP secretases (including ␦-and -secretases, alternative ␤-secretases) and additional metabolites, some of which may also cause synaptic dysfunction. Furthermore, various proteins have been identified that interact with APP and modulate its cleavage by the secretases. Here, we give an overview of the increasingly complex picture of APP proteolysis.Currently over 46 million people worldwide are living with dementia (see the Alzheimer's Disease International website) with Alzheimer disease (AD) 3 representing the most common form of dementia. In AD, the amyloid cascade hypothesis posits that amyloid-␤ (A␤), produced through the sequential proteolytic cleavage of the amyloid precursor protein (APP) by the ␤-and ␥-secretases, is a key molecule in initiating and propagating disease pathology including neurofibrillary tangle formation, neuronal cell loss, aberrant synaptic activity, and brain atrophy that lead to the clinically recognized symptoms of dementia (1). However, identification of the A␤ peptide 25 years ago has not yet led to the advent of a viable therapeutic strategy that can slow or halt the progression of AD. Recent studies have revealed new complexities in the proteolytic processing of APP, including the identification of novel secretases which generate APP metabolites that accumulate in the brains of AD patients and may contribute to the synaptic dysfunction observed in the disease. In addition, numerous proteins are being identified that interact with APP, modulating its proteolysis and A␤ production. These new APP secretases and metabolites, along with the APP interactors, may present novel therapeutic targets that are independent of direct modulation of the canonical secretases and that will need to be considered when evaluating the results from current A␤-directed therapies. In this Minireview, we summarize the recent developments in APP proteolysis focusing on the novel secretases, APP interactors, and APP metabolites that are impacting on our understanding of both APP biology and the neurodegenerative disease process. The Canonical ␣-, ␤-, and ␥-Secretases and APP FragmentsThe generally accepted model of APP proteolysis is that APP is processed by one of two distinct proteolytic pathways (Fig. 1A). In the amyloidogenic pathway, ␤-secretase, the ␤-site APP-cleaving enzyme 1 (BACE1), cleaves APP within the ectodomain and liberates a soluble proteolytic fragment, termed soluble APP␤ (sAPP␤), primarily in the endosomal system from the transmembrane APP holoprotein (2). The remaining C-terminal membrane-bound APP fragment, CTF␤, is subsequently cleaved by the presenilin (PS)-containing ␥-secretase multisubunit complex to liberate the A␤ peptide and the APP intrace...

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“…In addition, the APP N-terminal peptide/DR6 receptor interaction [66], APP δ-ɣ fragment [67,68], APP C-terminal peptides CT99/CT83 [69], Jcasp, P31 and the Aβ-related P3 [70] are neurotoxic or provoke neuronal apoptosis. Our preliminary observations suggest that in LOAD putatively toxic CT99/CT83 peptides, rather than Aβ, accumulate abundantly in cellular membranes as if they were not processed by the ɣ-secretase.…”

Section: Diverse Routes To Dementiamentioning

confidence: 99%

Alzheimer’s disease syndrome – Recognizing the complexity of dementia

Kokjohn¹,

Serrano²

2017

Neurol Disord Therap

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Therapies designed to disrupt amyloid plaque deposits or prevent their formation have yielded disappointing results against cognitive failure, suggesting that both our mechanistic models of dementia and interventions must become more nuanced. These treatments targeted Aβ40/42, but the amyloid accumulated in Alzheimer's disease patients is modified extensively and far more structurally diverse. Despite intensive work, the structure and physical state of the most toxic amyloid species remains mysterious. In addition, multiple lines of evidence suggest the genesis and progression of dementia is more complicated than the accumulation of senile plaques beyond a tolerable threshold. If amyloid plays key, but non-exclusive, roles in dementia pathogenesis this hypothesis must be addressed through investigations that are more holistic in scope. New imaging methods provide investigators unprecedented capabilities to detect and classify neuropathology in living subjects. Interpreting future clinical trial outcomes will hinge on correlating effects against dementia in subject cohorts that are precisely differentiated with respect to neuropathology and neurochemistry. Improving understanding of the comorbidities and the environmental/lifestyle factors foreshadowing cognitive failure will aid in the interpretation of clinical trials. Most important, as we seek an elusive cure for AD, these findings may be rapidly translatable into concrete and achievable public health improvements.

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Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease

Cited by 223 publications

References 64 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

A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

Alzheimer’s disease syndrome – Recognizing the complexity of dementia

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