Effects of Hypoxia and Oxidative Stress on Expression of Neprilysin in Human Neuroblastoma Cells and Rat Cortical Neurones and Astrocytes

Fisk, Lilia; Nalivaeva, Natalia N.; Boyle, John P.; Peers, Chris; Turner, Anthony J.

doi:10.1007/s11064-007-9349-2

Cited by 100 publications

(72 citation statements)

References 38 publications

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“…Here, we measured degradation of exogenous A␤ in SH-SY5Y cells, a human neuroblastoma cell line widely used for A␤ metabolism (19). As expected, exogenous A␤42 was degraded more efficiently (reduced to 36% of input substrate) in cells treated with 17␤-estradiol (100 nM for 24 h).…”

Section: ␤-Estradiol Enhances A␤42 Degradation and Up-regulatesmentioning

confidence: 54%

Estrogen Stimulates Degradation of β-Amyloid Peptide by Up-regulating Neprilysin

Liang

Yang

Yin

et al. 2010

Journal of Biological Chemistry

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Postmenopausal estrogen depletion is a characterized risk factor for Alzheimer disease (AD), a human disorder linked to high levels of ␤-amyloid peptide (A␤) in brain tissue. Previous studies suggest that estrogen negatively regulates the level of A␤ in the brain, but the molecular mechanism is unknown. Here, we provide evidence that estrogen promotes A␤ degradation mainly through a principal A␤ degrading enzyme, neprilysin, in neuroblastoma SH-SY5Y cells. We also demonstrate that upregulation of neprilysin by estrogen is dependent on both estrogen receptor ␣ and ␤ (ER␣ and ER␤), and ligand-activated ER regulates expression of neprilysin through physical interactions between ER and estrogen response elements (EREs) identified in the neprilysin gene. These results were confirmed by in vitro gel shift and in vivo chromatin immunoprecipitation analyses, which demonstrate specific binding of ER␣ and ER␤ to two putative EREs in the neprilysin gene. The EREs also enhance ER␣-and ER␤-dependent reporter gene expression in a yeast model system. Therefore, the study described here provides a putative mechanism by which estrogen positively regulates expression of neprilysin to promote degradation of A␤, reducing risk for AD. These results may lead to novel approaches to prevent or treat AD.Alzheimer disease (AD) 3 is a progressive neurodegenerative disease characterized by declarative memory impairment and progressive dementia. The level of ␤-amyloid peptide (A␤) is elevated in the brains of AD patients, and A␤ is believed to play a critical role in the pathology of AD (1, 2). Recent studies show that aggregated oligomers of A␤ (protofibrils) play a direct role in neuronal and behavioral deficits in AD patients (3).The rate of A␤ degradation could influence the risk of developing AD, and it has been proposed that stimulation of proteolytic degradation of A␤ could be used as a therapeutic approach for AD (4, 5). Neprilysin is thought to be the primary A␤-degrading enzyme in the brain (6) because degradation of radiolabeled synthetic A␤42 in rat brain is largely inhibited by the neprilysin inhibitor, phosphoramidon (PA) (7, 8) and because neprilysin degrades both monomeric and oligomeric forms of A␤40 and A␤42 in intracellular and extracellular compartments of the brain (9). Moreover, the level of neprilysin mRNA and protein is lower in the hippocampus and temporal gyrus of AD patients (10, 11), which correlates with higher levels of A␤ as A␤ tends to accumulate in these regions (12).Neprilysin activity is also lower in the hippocampus, cerebellum, and caudate of ovariectomized rats than in non-ovariectomized rats, and this effect can be reversed by exogenous 17␤-estradiol (13). These data indicate that 17␤-estradiol positively regulates neprilysin activity in the brain. 17␤-Estradiol was also reported to reduce the generation of A␤ peptides in neuroblastoma cells and neurons (14). The positive regulation of neprilysin by 17␤-estradiol might be a crucial factor in protecting normal adult brain from A␤ damage and in improving...

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Section: ␤-Estradiol Enhances A␤42 Degradation and Up-regulatesmentioning

confidence: 54%

Estrogen Stimulates Degradation of β-Amyloid Peptide by Up-regulating Neprilysin

Liang

Yang

Yin

et al. 2010

Journal of Biological Chemistry

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“…Анализируемые пробы добавляли в лунки 96-луночного планшета, в которые предварительно вносили реакционную смесь объемом 100 мкл, состоявшую из 50 мM HEPES буфера, 200 мM NaCl (pH 7,2) и 4 миллиединиц лейцинаминопептидазы (ЛАП, «Sigma»). Активность НЕП определялась по разни-це между флюоресценцией продукта, полученного в ре-зультате инкубации анализируемых проб без и в присут-ствии специфического ингибитора НЕП тиорфана (10 мкМ) [49]. Линейность реакции образования продукта оценивалась с помощью флюориметрии в присутствии избыточных количеств ЛАП, необходимых для создания условий, в которых скорость реакции лимитируется толь-ко присутствием анализируемого НЕП.…”

Section: материал и методыunclassified

The activity of blood serum cholinesterases and neprilysin as potential biomarkers of mild-cognitive impairment and Alzheimer’s disease

Журавин

Nalivaeva

Козлова

et al. 2015

Z. nevrol. psikhiatr. im. S.S. Korsakova

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“…It has been demonstrated that levels of expression and activity of the main proteases participating in brain Aβ metabolism in vivo, and especially of neprilysin (NEP; CD10), decline markedly with age, under hypoxia or ischemia and are even lower in AD patients (Caccamo et al 2005;Fisk et al 2007;Nalivaeva et al 2004;Wang et al 2010). In this regard, up-regulation of NEP and other amyloid-degrading enzymes is considered as a viable therapeutic strategy.…”

Section: Introductionmentioning

confidence: 99%

Effect of Sodium Valproate Administration on Brain Neprilysin Expression and Memory in Rats

et al. 2011

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Alzheimer's disease (AD) is accompanied by memory loss due to neuronal cell death caused by toxic amyloid β-peptide (Aβ) aggregates. In the healthy brain, a group of amyloid-degrading enzymes including neprilysin (NEP) maintain Aβ levels at physiologically low concentrations but, with age and under some pathological conditions, expression and activity of these enzymes decline predisposing to late-onset AD. Hence, up-regulation of NEP might be a viable strategy for prevention of Aβ accumulation and development of the disease. As we have recently shown, inhibitors of histone deacetylases, in particular, valproic acid (VA), were capable of up-regulating NEP expression and activity in human neuroblastoma SH-SY5Y cell lines characterised by very low levels of NEP. In the present study, analysing the effect of i.p. injections of VA to rats, we have observed up-regulation of expression and activity of NEP in rat brain structures, in particular, in the hippocampus. This effect was brain region- and age-specific. Administration of VA has also restored NEP activity and memory deficit in adult rats caused by prenatal hypoxia. This suggests that VA and more specific HDAC inhibitors can be considered as potential pharmaceutical agents for up-regulation of NEP activity and improvement of cognitive functions of ageing brain.

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Effects of Hypoxia and Oxidative Stress on Expression of Neprilysin in Human Neuroblastoma Cells and Rat Cortical Neurones and Astrocytes

Cited by 100 publications

References 38 publications

Estrogen Stimulates Degradation of β-Amyloid Peptide by Up-regulating Neprilysin

Estrogen Stimulates Degradation of β-Amyloid Peptide by Up-regulating Neprilysin

The activity of blood serum cholinesterases and neprilysin as potential biomarkers of mild-cognitive impairment and Alzheimer’s disease

Effect of Sodium Valproate Administration on Brain Neprilysin Expression and Memory in Rats

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