Oxidized neprilysin in aging and Alzheimer’s disease brains

Wang, Deng Shun; Iwata, Nobuhisa; Hama, Emi; Saido, Takaomi C.; Dickson, Dennis W.

doi:10.1016/j.bbrc.2003.09.003

Cited by 124 publications

(100 citation statements)

References 15 publications

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“…This differential effect may at least in part involve ROS-inactivation of the NEP enzyme through chemical adduct formation, while still allowing antibody detection of the NEP protein (19,55). ROS present in COPD lungs may come directly from cigarette smoke products, or may be generated in COPD lungs due to inflammatory responses or localized hypoxia (40,56,57).…”

Section: Discussionmentioning

confidence: 99%

Decreased Neprilysin and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease

Wick¹,

Buesing²,

Wehling³

et al. 2011

Am J Respir Crit Care Med

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Rationale: Studies with genetically engineered mice showed that decreased expression of the transmembrane peptidase neprilysin (NEP) increases susceptibility to hypoxic pulmonary vascular remodeling and hypertension; in hypoxic wild-type mice, expression is decreased early in distal pulmonary arteries, where prominent vascular remodeling occurs. Therefore, in humans with smoke-and hypoxia-induced vascular remodeling, as in chronic obstructive pulmonary disease (COPD), pulmonary activity/expression of NEP may likewise be decreased. Objectives: To test whether NEP activity and expression are reduced in COPD lungs and pulmonary arterial smooth muscle cells (SMCs) exposed to cigarette smoke extract or hypoxia and begin to investigate mechanisms involved. Methods: Control and advanced COPD lung lysates (n 5 13-14) were analyzed for NEP activity and protein and mRNA expression. As a control, dipeptidyl peptidase IV activity was analyzed. Lung sections were assessed for vascular remodeling and oxidant damage. Human pulmonary arterial SMCs were exposed to cigarette smoke extract, hypoxia, or H 2 O 2 , and incubated with antioxidants or lysosomal/proteasomal inhibitors. Measurements and Main Results: COPD lungs demonstrated areas of vascular rarification, distal muscularization, and variable intimal and prominent medial/adventitial thickening. NEP activity was reduced by 76%; NEP protein expression was decreased in alveolar walls and distal vessels; mRNA expression was also decreased. In SMCs exposed to cigarette smoke extract, hypoxia, and H 2 O 2 , NEP activity and expression were also reduced. Reactive oxygen species inactivated NEP activity; NEP protein degradation appeared to be substantially induced. Conclusions: Mechanisms responsible for reduced NEP activity and protein expression include oxidative reactions and protein degradation. Maintaining or increasing lung NEP may protect against pulmonary vascular remodeling in response to chronic smoke and hypoxia.Keywords: pulmonary hypertension; smooth muscle cell; smoking; oxidative stress; protein degradation Chronic obstructive pulmonary disease (COPD) is a leading cause of death; cigarette smoking is its number one risk factor (1). Pulmonary vascular remodeling, characterized by thickening, muscularization, and rarification of the distal vasculature (2-4), complicates COPD by contributing to pulmonary hypertension (PHTN) (3, 5). Many patients with COPD have mild PHTN at rest (6-8); however, the prevalence of exerciseinduced PHTN, which also may lead to right-sided heart failure in COPD (9), is much higher (. 91% [6,10]).COPD-associated PHTN is likely caused by initial injury of the pulmonary vascular endothelium by cigarette smoke (CS) (4), followed by inflammation and hypoxia, all of which may involve oxidant mechanisms (11,12). Factors that may contribute to variable susceptibility to COPD-associated PHTN, including interleukin-6 (IL-6) and the serotonin transporter (5HTT) (6,10,13,14), have been extensively investigated.Neprilysin (NEP, CD10) is a transmembrane ...

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Section: Discussionmentioning

confidence: 99%

Decreased Neprilysin and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease

Wick¹,

Buesing²,

Wehling³

et al. 2011

Am J Respir Crit Care Med

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“…and the Veteran's Administration (Merit Review to M.S.K.). the early stages of AD development, [17][18][19] accompanied with aging, 19,20 genetic deficiency (knockout), 6 or treatment with NEP in the inhibitors, 21,22 results in increasing the accumulation of A␤ peptide in the brain and thus led to memory impairment. Therefore, increasing the expression or activity of NEP in the early phase of the disease may reverse or halt the disease onset.…”

mentioning

confidence: 99%

Neprilysin: An Enzyme Candidate to Slow the Progression of Alzheimer's Disease

El‐Amouri

Zhu

et al. 2008

The American Journal of Pathology

163

132

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It is well established that the extracellular deposition of amyloid ␤ (A␤) peptide plays a central role in the development of Alzheimer's disease (AD). Therefore, either preventing the accumulation of A␤ peptide in the brain or accelerating its clearance may slow the rate of AD onset. Neprilysin (NEP) is the dominant A␤ peptide-degrading enzyme in the brain; NEP becomes inactivated and down-regulated during both the early stages of AD and aging. In this study, we investigated the effect of human (h)NEP gene transfer to the brain in a mouse model of AD before the development of amyloid plaques, and assessed how this treatment modality affected the accumulation of A␤ peptide and associated pathogenetic changes (eg, inflammation, oxidative stress, and memory impairment). Overexpression of hNEP for 4 months in young APP/⌬PS1 double-transgenic mice resulted in reduction in A␤ peptide levels, attenuation of amyloid load, oxidative stress, and inflammation, and improved spatial orientation. Moreover, the overall reduction in amyloidosis and associated pathogenetic changes in the brain resulted in decreased memory impairment by ϳ50%. These data suggest that restoring NEP levels in the brain at the early stages of AD is an effective strategy to prevent or attenuate disease progression. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a loss of neurons in discrete regions of the brain, particularly in the cortex and hippocampus.1,2 The neuronal loss is accompanied by extracellular deposition of A␤ peptide in a form of senile plaques and intracellular accumulation of neurofibrillary tangles made of a hyperphosphorylated form of the microtubule-associated protein tau.3 Clinically, AD is characterized by a gradual decline in cognition, and changes in behavior and personality including difficulty in reasoning, disorientation, and language problems. The exact cause of AD is not yet clear, but it is widely assumed that accumulation and aggregation of A␤ peptide is the initial trigger for a complex, multistep cascade that includes gliosis, inflammatory changes, oxidative stress, neuritic/ synaptic changes, tangle formation (microtubule changes), and neurotransmitter loss, leading to dementia. 4 Therefore, lowering the A␤ peptide levels in the brain would stop or delay the onset of AD. NEP as one of the A␤ peptide-degrading enzymes, has been reported to play a key role in regulating the level of A␤ peptide in the brain. 5,6 NEP [neprilysin, previously called CD10 or common acute lymphoblastic leukemia antigen (CALLA)] is a type II membrane metalloendopeptidase composed of ϳ750 residues (ϳ110 kDa) with an active site containing a zinc-binding motif (HEXXH) at the extracellular carboxyl terminal domain.7-10 NEP is capable of degrading the monomeric and (possibly) the oligomeric forms of A␤ peptide. 11,12 In recent years several reports have indicated that the soluble (eg, oligomeric) forms of A␤ peptide play a significant role in memory impairment and AD, [13][14][15] however, it is noteworthy t...

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“…Oxidative stress, in which production of highly reactive oxygen species overwhelms antioxidant defenses, has been increasingly implicated in a number of neurodegenerative disorders characterized by deposition of abnormal forms of specific proteins in affected neurons, including Parkinson disease, Alzheimer disease, Pick disease, other Lewy body diseases, amyotrophic lateral sclerosis, and Huntington disease (32)(33)(34)(35)(36)(37)(38). Reactive oxygen species induce peroxidation of lipids (cellular membrane lipids or circulating lipoprotein molecules), generating highly reactive aldehydes (39).…”

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confidence: 99%

Effect of 4-Hydroxy-2-nonenal Modification on α-Synuclein Aggregation

Qin

Han

et al. 2007

Journal of Biological Chemistry

173

159

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Several observations have implicated oxidative stress and aggregation of the presynaptic protein ␣-synuclein in the pathogenesis of Parkinson disease. ␣-Synuclein has been shown to have affinity for unsaturated fatty acids and membranes enriched in polyunsaturated fatty acids, which are especially sensitive to oxidation under conditions of oxidative stress. One of the most important products of lipid oxidation is 4-hydroxy-2-nonenal (HNE), which has been implicated in the pathogenesis of Parkinson disease. Consequently, we investigated the effects of the interaction of HNE with ␣-synuclein. Incubation of HNE with ␣-synuclein at pH 7.4 and 37°C resulted in covalent modification of the protein, with up to six HNE molecules incorporated as Michael addition products. Fourier transform infrared and CD spectra indicated that HNE modification of ␣-synuclein resulted in a major conformational change involving increased ␤-sheet. HNE modification of ␣-synuclein led to inhibition of fibrillation in an HNE concentration-dependent manner. This inhibition of fibrillation was shown to be due to the formation of soluble oligomers based on size exclusion high pressure liquid chromatography and atomic force microscope data. Small angle x-ray scattering analysis indicated that the HNE-induced oligomers were compact and tightly packed. Treatment with guanidinium chloride demonstrated that the HNE-induced oligomers were very stable with an extremely slow rate of dissociation. Addition of 5 M HNE-modified oligomers to primary mesencephalic cultures caused marked neurotoxicity because the integrity of dopaminergic and GABAergic neurons was reduced by 95 and 85%, respectively. Our observations indicate that HNE modification of ␣-synuclein prevents fibrillation but may result in toxic oligomers, which could therefore contribute to the demise of neurons subjected to oxidative damage.

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Oxidized neprilysin in aging and Alzheimer’s disease brains

Cited by 124 publications

References 15 publications

Decreased Neprilysin and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease

Decreased Neprilysin and Pulmonary Vascular Remodeling in Chronic Obstructive Pulmonary Disease

Neprilysin: An Enzyme Candidate to Slow the Progression of Alzheimer's Disease

Effect of 4-Hydroxy-2-nonenal Modification on α-Synuclein Aggregation

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