Regular articleNardilysin prevents amyloid plaque formation by enhancing α-secretase activity in an Alzheimer's disease mouse model
Introduction
Amyloid beta (Aβ) peptide deposition in the extracellular region is one of the pathological hallmarks of Alzheimer's disease (AD). Aβ is derived from sequential cleavage of the amyloid precursor protein (APP), ectodomain shedding by β-secretase, and intramembrane cleavage by γ-secretase (Haass, 2004, Querfurth and LaFerla, 2010, Selkoe and Schenk, 2003). As ectodomain shedding of APP by α-secretase occurs within the Aβ domain, it has the potential to preclude generation of the Aβ peptide. In addition, a secreted fragment of APP generated by α-cleavage (sAPPα) was shown to have neurotrophic and neuroprotective properties (Furukawa et al., 1996, Stein et al., 2004). An enhancement in α-secretase activity is considered to be a therapeutic approach for AD (Fahrenholz, 2007, Lichtenthaler, 2011). Several members of the ‘a disintegrin and metalloprotease’ (ADAM) family, such as ADAM9, ADAM10, and ADAM17, have been reported to exhibit α-secretase activity (Kim et al., 2008). However, results from 2 recent studies, one using gene knockdown in primary neurons and the other using neurons derived from ADAM10 conditional knockout mice, demonstrated that the main α-secretase appears to be ADAM10 (Jorissen et al., 2010, Kuhn et al., 2010). Furthermore, ADAM10 overexpression in the AD mouse model reduced Aβ deposition, which indicated that activation of α-secretase is beneficial for the prevention of AD (Postina et al., 2004).
Nardilysin (EC 3.4.24.61; N-arginine dibasic convertase; NRDc) was initially identified as a metalloendopeptidase of the M16 family (Chesneau et al., 1994, Pierotti et al., 1994). We rediscovered NRDc as a specific binding partner of heparin-binding EGF-like growth factor (HB-EGF) (Nishi et al., 2001), and demonstrated that NRDc enhances ectodomain shedding of HB-EGF through activation of ADAM17 (Nishi et al., 2006). In our subsequent studies, we showed that ectodomain shedding of multiple membrane proteins such as tumor necrosis factor-alpha (TNF-α) and APP is also enhanced by NRDc (Hiraoka et al., 2007, Hiraoka et al., 2008). Regarding APP, NRDc enhanced ADAM9-, ADAM10-, and ADAM17-induced α-cleavage, which resulted in the decreased generation of Aβ in vitro (Hiraoka et al., 2007).
We demonstrated using NRDc-deficient mice (Nrd1−/−) that NRDc regulates myelination through the modulation of neuregulin-1 (NRG1) shedding. Similar to APP, the membrane precursor of NRG1 is shown to be cleaved by ADAMs (α-secretase) and beta-site APP-cleaving enzyme 1 (BACE1) (β-secretase) at 2 adjacent sites (Luo et al., 2011, Willem et al., 2006). We showed that ectodomain shedding of NRG1 is impaired in Nrd1−/− fibroblasts and brains. Moreover, gain of function experiments in cells revealed that NRDc enhances ADAM17- and BACE1-mediated NRG1 shedding (Ohno et al., 2009). These findings suggested that NRDc is able to modulate α- and β-secretase activity.
Here, to clarify the pathophysiological role of NRDc in AD, we evaluated the in vivo effect of NRDc overexpression or deletion on α- and β-secretase activity. We found that NRDc controls Aβ formation by mainly regulating α-secretase in vivo.
Section snippets
Animals
Transgenic mice expressing mouse NRDc under the control of a forebrain neuron-specific calcium/calmodulin-dependent protein kinase II alpha (CamkIIα) promoter and NRDc-deficient mice (CDB0466K: http://www.cdb.riken.jp/arg/mutant%20mice%20list.html) were described previously (Ohno et al., 2009). APP transgenic mice (APP-Tg) overexpressing human APP695swe and the mutant presenillin1 (PS1-dE9) were obtained from Jackson Laboratories (B6C3-Tg, APPswe, PSEN1dE9; 85Dbo/Mmjax, stock number: 004462),
Enhanced NRDc expression reduces Aβ deposition in the forebrain of the AD mouse model
We generated transgenic mice expressing mouse NRDc under the control of a forebrain neuron-specific CamkIIα promoter (NRDc-Tg) (Ohno et al., 2009). Although NRDc-Tg mice show hypermyelination especially in the corpus callosum, they exhibited no behavioral abnormalities throughout their life span. To examine the pathophysiological effects of NRDc overexpression on AD progression, we intercrossed NRDc-Tg with AD model mice (APP-Tg: transgenic mice expressing APP695swe and a mutant presenillin1
Discussion
Our findings provide the first in vivo evidence that a metalloendopeptidase NRDc prevents amyloid plaque formation in the AD mouse model. Forebrain neuron-specific NRDc overexpression increased the level of sAPPα and reduced Aβ deposition, indicating that NRDc precludes Aβ deposition through the activation of α-secretases. NRDc overexpression in NRDc-Tg mice was only modest (2- to 3-fold higher than that in wild type mice), suggesting the physiological role of NRDc in the regulation of
Disclosure statement
The authors have no actual or potential conflicts of interest.
All experiments with mice followed the Institute's guidelines for animals and were approved by the Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University.
Acknowledgements
The authors thank T. Kihara for providing materials. This study was supported by Research grants (23300117, 23117519, 23659154, 23122510, 22800037, and 24700366) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. It was also supported by the Takeda Science Foundation, Mitsui Sumitomo Insurance Welfare Foundation, Suzuken Memorial Foundation, Daiichi Sankyo Sponsored Research Program, and by Program KNDD/BMBF to S.F.L.
References (29)
- et al.
N-arginine dibasic convertase (NRD convertase): a newcomer to the family of processing endopeptidases. An overview
Biochimie
(1994) - et al.
Ectodomain shedding of TNF-alpha is enhanced by nardilysin via activation of ADAM proteases
Biochem. Biophys. Res. Commun.
(2008) - et al.
Cleavage of neuregulin-1 by BACE1 or ADAM10 protein produces differential effects on myelination
J. Biol. Chem.
(2011) - et al.
Transcriptional profiling of Alzheimer blood mononuclear cells by microarray
Neurobiol. Aging
(2007) - et al.
Nardilysin enhances ectodomain shedding of heparin-binding epidermal growth factor-like growth factor through activation of tumor necrosis factor-alpha-converting enzyme
J. Biol. Chem.
(2006) - et al.
Amyloid precursor protein trafficking, processing, and function
J. Biol. Chem.
(2008) - et al.
Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition
FASEB J.
(2009) - et al.
Constitutive alpha- and beta-secretase cleavages of the amyloid precursor protein are partially coupled in neurons, but not in frequently used cell lines
Neurobiol. Dis.
(2012) Alpha-secretase as a therapeutic target
Curr. Alzheimer Res.
(2007)- et al.
Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain
J. Neurochem.
(1996)
Take five–BACE and the gamma-secretase quartet conduct Alzheimer's amyloid beta-peptide generation
EMBO J.
Enhancement of alpha-secretase cleavage of amyloid precursor protein by a metalloendopeptidase nardilysin
J. Neurochem.
The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex
J. Neurosci.
Nardilysin and ADAM proteases promote gastric cancer cell growth by activating intrinsic cytokine signalling via enhanced ectodomain shedding of TNF-alpha
EMBO Mol. Med.
Cited by (29)
Nardilysin determines hematopoietic stem cell fitness by regulating protein synthesis
2024, Biochemical and Biophysical Research CommunicationsChronic MC-LR exposure promoted Aβ and p-tau accumulation via regulating Akt/GSK-3β signal pathway
2021, Science of the Total EnvironmentCitation Excerpt :Aβ is cleaved from amyloid precursor protein (APP) through two processes regulated by β-secretase (BACE1) and γ-secretase (presenilin complex) (Zhang et al., 2011). Additionally, proteins of a disintegrin and metalloprotease (ADAM) family (Lammich et al., 1999), especially ADAM9, 10 and 17, contribute to APP cleavage as α-secretase, precluding Aβ generation (Hiraoka et al., 2007; Ohno et al., 2014). Tau locates in the neuronal axons, binds to and stabilizes the microtubules in the neurons.
Clinical determination of serum nardilysin levels in predicting 30-day mortality among adults with malignant cerebral infarction
2019, Clinica Chimica ActaCitation Excerpt :Such evidence shows that nardilysin might be involved in inflammatory response of human diseases. In fact, nardilysin can be expressed widely in human brain neurons [41] and also participates in human brain diseases, e.g., Alzheimer's disease, Down syndrome, schizophrenia, mood disorders and alcohol abuse [34–39]. However, there are no previous data regarding serum nardilysin concentrations in patients with brain injury.
Nardilysin is a promising biomarker for the early diagnosis of acute coronary syndrome
2017, International Journal of CardiologyCitation Excerpt :NRDC is a metalloendopeptidase of the M16 family, which was identified as a binding protein of HB-EGF [6]. NRDC is secreted from cells and enhances ectodomain shedding of multiple membrane proteins such as TNF-α, HB-EGF, NRG1, and APP [7–9]. NRDC has thus far been suggested to have important roles in inflammatory diseases [10,11].
Chronic sleep fragmentation exacerbates amyloid β deposition in Alzheimer's disease model mice
2017, Neuroscience LettersCitation Excerpt :The sections were colorized using 3,3'-diaminobenzidine tetrahydrochloride (Dojindo Laboratories, Kumamoto, Japan) solution containing 0.03% hydrogen peroxide, counterstained with hematoxylin and examined with bright-field microscopy (BZ-X710, Keyence, Osaka, Japan). Aβ plaques in the whole brain section was quantitatively analyzed as previously described [20] using dedicated software (Hybrid Cell Count System BA-H3C, Keyence), with the experimenter (H.Y.) blinded to the experimental group. The plaque load was calculated as the percentage of the total plaque area within the total brain surface area of the corresponding section.
Association of gene expression and methylation of UQCRC1 to the predisposition of Alzheimer's disease in a Chinese population
2016, Journal of Psychiatric ResearchCitation Excerpt :The result suggested these genes might be involved in the signaling cascade modulating the pathology of AD. NRD1 was shown to enhance APP α-cleavage resulting in the decrease of Aβ (Hiraoka et al., 2007; Ohno et al., 2014). CTSB was shown to increase Aβ degradation in mouse model (Wang et al., 2012).