Putative function of ADAM9, ADAM10, and ADAM17 as APP  -secretase

Asai, Manabu; Hattori, Chinatsu; Szabó, Beáta; Sasagawa, Noboru; Maruyama, Kei; Tanuma, Sei Ichi; Ishiura, Shoichi

doi:10.1016/s0006-291x(02)02999-6

Cited by 274 publications

(177 citation statements)

References 32 publications

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“…Although we demonstrated that ADAM10 was more potent than ADAM17 in shedding Nrg1 and a recent study also demonstrates that ADAM10 is a physiologically relevant ␣-secretase that processes APP constitutively (30), we can not exclude the compensatory processing of Nrg1 by ADAM17 or other ADAM proteases. Second, both ADAM10 and ADAM17 can function as an ␣-secretase (22,23), an observation similar to that obtained in this study. Despite the fact that ADAM10 is a more abundant protease in the axon (26), the presence of ADAM17 and other not yet characterized ADAM proteases may compensate for the loss of ADAM10 in ADAM10-null mice.…”

Section: Discussionsupporting

confidence: 89%

“…BACE1 is the only protease that cleaves APP at the ␤-secretase site, whereas three proteases (ADAM9, ADAM10, and ADAM17) are reported to process APP at an identical ␣-secretase site (22,23). To test our hypothesis, we incubated either ADAM10 or ADAM17 protease with a recombinant protein spanning the entire extracellular domain of human Nrg1 in an enzymatic assay.…”

Section: Resultsmentioning

confidence: 99%

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Cleavage of Neuregulin-1 by BACE1 or ADAM10 Protein Produces Differential Effects on Myelination

Luo

Prior

et al. 2011

Journal of Biological Chemistry

107

117

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Neuregulin-1 (Nrg1) is encoded by a single gene and exists in naturally secreted and transmembrane isoforms. Nrg1 exerts its signaling activity through interaction with its cognate ErbB receptors. Multiple membrane-anchored Nrg1 isoforms, present in six different membrane topologies, must be processed by a protease to initiate a signaling cascade. Here, we demonstrate that BACE1 and ADAM10 can process type I and III Nrg1 at two adjacent sites. Our cleavage site mapping experiments showed that the BACE1 cleavage site is located eight amino acids downstream of the ADAM10 cleavage site, and this order of cleavage is the opposite of amyloid precursor protein cleavage by these two enzymes. Cleavages were further confirmed via optimized electrophoresis. Cleavage of type I or III Nrg1 by ADAM10 and BACE1 released a signaling-capable N-terminal fragment (ntf), either Nrg1-ntf␣ or Nrg1-ntf␤, which could similarly activate an ErbB receptor as evidenced by increased phosphorylation of Akt and ERK, two downstream signaling molecules. Although both Nrg1-ntf␣ and Nrg1-ntf␤ could initiate a common signaling cascade, inhibition or down-regulation of ADAM10 alone in a co-culture system did not affect normal myelination, whereas specific inhibition of BACE1 impaired normal myelination. Thus, processing of Nrg1 by BACE1 appears to be more critical for regulating myelination. Our results imply that a significant inhibition of BACE1 could potentially impair Nrg1 signaling activity in vivo. Members of the neuregulin (Nrg)3 family of proteins contain an EGF-like domain that mediates cell-cell signaling functions via interaction with cognate ErbB receptors (1, 2). The Nrg protein family consists of four members (Nrg1-Nrg4), with Nrg1 being the most well characterized. Because of multiple splicing events, mammalian Nrg1 has a total of 33 isoforms that can be distinguished by six different membrane topologies (types I-VI) (3). Mice with a genetic deletion of Nrg1 are embryonic-lethal due to circulatory failure and defects in neural and cardiac development (4), indicating the importance of Nrg1 in normal growth. As a critical signaling molecule, Nrg1 has also been linked to developmental abnormalities and pathogenesis of multiple diseases. For example, Nrg1 polymorphism has been identified as a risk factor for schizophrenia (5).Mouse genetic studies also demonstrate that type III Nrg1 is a master regulator of myelination; its level in axons is correlated with the thickness of the myelin sheath (6, 7).Most of the 33 Nrg1 isoforms are membrane-anchored ligands, and proteolytic cleavage of these membrane-bound Nrg1 isoforms is required for the secreted Nrg1 fragment to bind to its cognate receptor, an ErbB2/ErbB3 heterodimer or ErbB4 homodimer (8 -10). In our recent study of Alzheimer ␤-secretase (BACE1), we demonstrated that membrane-anchored type I and III ␤1 Nrg1 isoforms are cleaved by BACE1 at the site between residues EF and ME, ϳ10 residues away from the transmembrane region (11). In BACE1-null mice, the cleavage of type I and III ␤1 ...

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Cleavage of Neuregulin-1 by BACE1 or ADAM10 Protein Produces Differential Effects on Myelination

Luo

Prior

et al. 2011

Journal of Biological Chemistry

107

117

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“…Interestingly, ADAM9 transient transfection also drastically increases sAPP␣ recovery in ␤APP-expressing HEK293 cells (Fig. 1, B and D), thereby confirming that in HEK293 cells, ADAM9 could participate to the ␣-secretase-mediated cleavage of ␤APP as it did in COS cells and human glioblastoma A172 cells (21,29).…”

Section: Transient and Stable Transfections Of Adam9 Cdna Increases N1supporting

confidence: 62%

The Disintegrin ADAM9 Indirectly Contributes to the Physiological Processing of Cellular Prion by Modulating ADAM10 Activity

Cissé

Sunyach

Lefranc-Jullien

et al. 2005

Journal of Biological Chemistry

106

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The cellular prion protein (PrP c ) is physiologically cleaved in the middle of its 106 -126 amino acid neurotoxic region at the 110/ 1112112 peptidyl bond, yielding an N-terminal fragment referred to as N1. We recently demonstrated that two disintegrins, namely ADAM10 and ADAM17 (TACE, tumor necrosis factor alpha converting enzyme) participated in both constitutive and protein kinase C-regulated generation of N1, respectively. These proteolytic events were strikingly reminiscent of those involved in the socalled "␣-secretase pathway" that leads to the production of secreted sAPP␣ from ␤APP. We show here, by transient and stable transfection analyses, that ADAM9 also participates in the constitutive secretion of N1 in HEK293 cells, TSM1 neurons, and mouse fibroblasts. Decreasing endogenous ADAM9 expression by an antisense approach drastically reduces both N1 and sAPP␣ recoveries. However, we establish that ADAM9 was unable to increase N1 and sAPP␣ productions after transient transfection in fibroblasts depleted of ADAM10. Accordingly, ADAM9 is unable to cleave a fluorimetric substrate of membrane-bound ␣-secretase activity in ADAM10 ؊/؊ fibroblasts. However, we establish that co-expression of ADAM9 and ADAM10 in ADAM10-deficient fibroblasts leads to enhanced membrane-bound and released fluorimetric substrate hydrolyzing activity when compared with that observed after ADAM10 cDNA transfection alone in ADAM10 ؊/؊ cells. Interestingly, we demonstrate that shedded ADAM10 displays the ability to cleave endogenous PrP c in fibroblasts. Altogether, these data provide evidence that ADAM9 is an important regulator of the physiological processing of PrP c and ␤APP but that this enzyme acts indirectly, likely by contributing to the shedding of ADAM10. ADAM9 could therefore represent, besides ADAM10, another potential therapeutic target to enhance the breakdown of the 106 -126 and A␤ toxic domains of the prion and ␤APP proteins.Spongiform encephalopathies are fatal neurodegenerative diseases involving a highly protease-resistant protein referred to as prion scrapie (PrP sc ) 4 (1, 2). Human prion diseases include, among others, Creutzfeldt-Jakob disease, familial transmissible spongiform encephalopathies, new variant of Creutzfeldt-Jakob disease, as well as a few cases of iatrogenic transmission (3-5). PrP sc corresponds to the abnormal conformation of an ubiquitous glycosylphosphatidylinositol-anchored protein called cellular prion (PrP c ) that is mainly synthesized in the central nervous system (6, 7). The mechanisms by which PrP c is converted into PrP sc are not fully understood. However, it appears clearly that inoculation of PrP sc triggers pathology and ultimately cell death in mice only when PrP c is present in the host animal. Thus, PrP c null mice resist infection and toxicity exhibited by scrapie-enriched inoculates (8 -10). On the other hand, it appears that depletion of PrP c is relatively innocuous (11,12). Therefore, all strategies aimed at lowering endogenous PrP c are potential therapeutic approaches. Clas...

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“…3 for review). The identity of α-secretase remains unclear although TACE (an enzyme responsible for cleavage of members of the TNF receptor family at the cell surface) and ADAM9 and ADAM10 are candidates 64,65 . Cleavage of APP by α-secretase releases sAPPα from the cell surface and leaves an 83 amino acid C-terminal APP fragment (C83).…”

Section: Boxmentioning

confidence: 99%

Pathways towards and away from Alzheimer's disease

Mattson

2004

Nature

2,784

2,058

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Slowly, but surely, Alzheimer's disease (AD) patients lose their memory, their cognitive abilities and even their personalities may change dramatically. These changes are due to the progressive dysfunction and death of nerve cells that are responsible for the storage and processing of information. While drugs can temporarily improve memory, at present there are no treatments that can stop or reverse the inexorable neurodegenerative process. But rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise is increasing optimism that effective preventative and therapeutic strategies are in the offing.Alzheimer's disease (AD) is a neurodegenerative disorder that currently affects nearly 2% of the population in industrialized countries; the risk of AD dramatically increases in individuals beyond the age of 70 and it is predicted that the incidence of AD will triple within the next 50 years (www.alz.org). There can be other causes of memory loss and definitive diagnosis of AD therefore requires postmortem examination of the brain, which must contain sufficient numbers of "plaques" and "tangles" to qualify as AD 1, 2 . Plaques are extracellular deposits of fibrils and amorphous aggregates of amyloid β-peptide (Aβ); diffuse deposits of Aβ are also present in high amounts. Neurofibrillary tangles are intracellular fibrillar aggregates of the microtubule-associated protein tau which exhibit hyperphosphorylation and oxidative modifications. Plaques and tangles are present mainly in brain regions involved in learning and memory and emotional behaviors such as the entorhinal cortex, hippocampus, basal forebrain and amygdala. Brain regions with plaques typically exhibit reduced numbers of synapses, and neurites associated with the plaques are often damaged, suggesting that Aβ damages synapses and neurites. Neurons that employ glutamate or acetylcholine as neurotransmitters appear to be particularly affected, but neurons that produce serotonin and norepinephrine are also damaged. This review focuses on the molecular and cellular abnormalities that occur in the brain in AD, how they result in synaptic dysfunction and cell death, and how they can be counteracted. Central to the disease is altered proteolytic processing of the amyloid precursor protein (APP) resulting in the production and aggregation of neurotoxic forms of Aβ. Neurons that degenerate in AD exhibit increased oxidative damage, impaired energy metabolism and perturbed cellular calcium homeostasis; Aβ appears to be an important instigator of these abnormalities. Genetic and environmental factors can determine one's risk for and an understanding of these risk factors and how they modify the amyloid cascade is leading to the development of interventions for the prevention and treatment of AD that range from changes in diet and lifestyle, to vaccines and drugs.

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Putative function of ADAM9, ADAM10, and ADAM17 as APP -secretase

Cited by 274 publications

References 32 publications

Cleavage of Neuregulin-1 by BACE1 or ADAM10 Protein Produces Differential Effects on Myelination

Cleavage of Neuregulin-1 by BACE1 or ADAM10 Protein Produces Differential Effects on Myelination

The Disintegrin ADAM9 Indirectly Contributes to the Physiological Processing of Cellular Prion by Modulating ADAM10 Activity

Pathways towards and away from Alzheimer's disease

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