Alzheimer's Disease and NQO1: Is there a Link?

Chhetri, Jamuna; King, Anna E.; Gueven, Nuri

doi:10.2174/1567205014666170203095802

Cited by 32 publications

(23 citation statements)

References 128 publications

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“…While Xn appears to have multiple physiological and therapeutic potential, any effective secondary prevention or treatment of AD will require long-term therapy with minimal adverse side effects. In this regard, it is noteworthy that Xn, acting as a weak electrophile Michael acceptor, is thought to exert chemopreventive effects via induction of detoxification enzymes such as NADPH quinone oxidoreductase 1 (NQO1) ( Dietz and Bolton, 2011 ), which has also been associated with AD ( Chhetri et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

The Prenylflavonoid Xanthohumol Reduces Alzheimer-Like Changes and Modulates Multiple Pathogenic Molecular Pathways in the Neuro2a/APPswe Cell Model of AD

et al. 2018

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that has proved refractory to drug treatment. Given evidence of neuroprotection in animal models of ischemic stroke, we assessed the prenylflavonoid xanthohumol from the Common Hop (Humulus lupulus L.) for therapeutic potential in murine neuroblastoma N2a cells stably expressing human Swedish mutant amyloid precursor protein (N2a/APP), a well-characterized cellular model of AD. The ELISA and Western-blot analysis revealed that xanthohumol (Xn) inhibited Aβ accumulation and APP processing, and that Xn ameliorated tau hyperphosphorylation via PP2A, GSK3β pathways in N2a/APP cells. The amelioration of tau hyperphosphorylation by Xn was also validated on HEK293/Tau cells, another cell line with tau hyperphosphorylation. Proteomic analysis (2D-DIGE-coupled MS) revealed a total of 30 differentially expressed lysate proteins in N2a/APP vs. wild-type (WT) N2a cells (N2a/WT), and a total of 21 differentially expressed proteins in lysates of N2a/APP cells in the presence or absence of Xn. Generally, these 51 differential proteins could be classified into seven main categories according to their functions, including: endoplasmic reticulum (ER) stress-associated proteins; oxidative stress-associated proteins; proteasome-associated proteins; ATPase and metabolism-associated proteins; cytoskeleton-associated proteins; molecular chaperones-associated proteins, and others. We used Western-blot analysis to validate Xn-associated changes of some key proteins in several biological/pathogenic processes. Taken together, we show that Xn reduces AD-related changes in stably transfected N2a/APP cells. The underlying mechanisms involve modulation of multiple pathogenic pathways, including those involved in ER stress, oxidative stress, proteasome molecular systems, and the neuronal cytoskeleton. These results suggest Xn may have potential for the treatment of AD and/or neuropathologically related neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

The Prenylflavonoid Xanthohumol Reduces Alzheimer-Like Changes and Modulates Multiple Pathogenic Molecular Pathways in the Neuro2a/APPswe Cell Model of AD

et al. 2018

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Section: Nicotinamide Adenine Dinucleotide Phosphate (Nadph)mentioning

confidence: 99%

“…Endogenous antioxidant systems decrease with aging, favoring the appearance of AD. Therefore, oxidative stress is at the heart of AD pathogenesis [12,13].…”

Section: Introductionmentioning

confidence: 99%

“…NADPH quinone oxidoreductase 1 (NQO1) is a flavin adenine dinucleotide- (FAD-) dependent cytoplasmic flavoprotein that catalyzes the reduction of two electrons from quinones, quinonimines, and nitroaromatic naphthoquinones and substituted by glutathione, dichlorophenolindophenol (DCPIP) dyes, and an NADPH as an electron donor [ 12 ]. Therefore, NQO1, plays a central role in monitoring cellular redox status, protecting against oxidative stress induced by a variety of metabolic situations [ 44 ], including the metabolism of quinones and other xenobiotics, through the following mechanisms: (i) functioning as a two-electron donor, to provide a derivation that competes with the formation of ROS; (ii) maintaining reduced coenzyme Q; and (iii) regulating the stress-activated kinase pathway [ 45 ].…”

Section: Introductionmentioning

confidence: 99%

“…According to Chhetri et al [ 12 ], the inactivation of the detoxifying enzyme NQO1 has been linked to the progression of AD. Factors that alter NQO1 activity can include genetic predispositions, such as the C690T NQO1 polymorphism, advanced age, cigarette smoking, and various medications [ 12 ]. The early expression of NQO1 in astrocytes may reflect a partially protective neuronal cell antioxidant protection system that activates at the beginning of the disease process, whereas the late expression of NQO1 may indicate the delayed activation of this system, as a final attempt to prevent neuronal cell death [ 46 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Identification of New Targets and the Virtual Screening of Lignans against Alzheimer’s Disease

Maia

Rodrigues

Sousa

et al. 2020

Oxidative Medicine and Cellular Longevity

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Alzheimer’s disease (AD) is characterized by the progressive disturbance in cognition and affects approximately 36 million people, worldwide. However, the drugs used to treat this disease are only moderately effective and do not alter the course of the neurodegenerative process. This is because the pathogenesis of AD is mainly associated with oxidative stress, and current drugs only target two enzymes involved in neurotransmission. Therefore, the present study sought to identify potential multitarget compounds for enzymes that are directly or indirectly involved in the oxidative pathway, with minimal side effects, for AD treatment. A set of 159 lignans were submitted to studies of QSAR and molecular docking. A combined analysis was performed, based on ligand and structure, followed by the prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. The results showed that the combined analysis was able to select 139 potentially active and multitarget lignans targeting two or more enzymes, among them are c-Jun N-terminal kinase 3 (JNK-3), protein tyrosine phosphatase 1B (PTP1B), nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1), NADPH quinone oxidoreductase 1 (NQO1), phosphodiesterase 5 (PDE5), nuclear factor erythroid 2-related factor 2 (Nrf2), cycloxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS). The authors conclude that compounds (06) austrobailignan 6, (11) anolignan c, (19) 7-epi-virolin, (64) 6-[(2R,3R,4R,5R)-3,4-dimethyl-5-(3,4,5-trimethoxyphenyl)oxolan-2-yl]-4-methoxy-1,3-benzodioxole, (116) ococymosin, and (135) mappiodoinin b have probabilities that confer neuroprotection and antioxidant activity and represent potential alternative AD treatment drugs or prototypes for the development of new drugs with anti-AD properties.

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Structural dynamics at the active site of the cancer‐associated flavoenzyme NQO1 probed by chemical modification with PMSF

Grieco,

Ruiz‐Fresneda,

Gómez‐Mulas

et al. 2023

FEBS Letters

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A large conformational heterogeneity of human NAD(P)H:quinone oxidoreductase 1 (NQO1), a flavoprotein associated with various human diseases, has been observed to occur in the catalytic site of the enzyme. Here, we report the X‐ray structure of NQO1 with phenylmethylsulfonyl fluoride (PMSF) at 1.6 Å resolution. Activity assays confirmed that, despite being covalently bound to the Tyr128 residue at the catalytic site, PMSF did not abolish NQO1 activity. This may indicate that the PMSF molecule does not reduce the high flexibility of Tyr128, thus allowing NADH and DCPIP substrates to bind to the enzyme. Our results show that targeting Tyr128, a key residue in NQO1 function, with small covalently bound molecules could possibly not be a good drug discovery strategy to inhibit this enzyme.

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Alzheimer's Disease and NQO1: Is there a Link?

Cited by 32 publications

References 128 publications

The Prenylflavonoid Xanthohumol Reduces Alzheimer-Like Changes and Modulates Multiple Pathogenic Molecular Pathways in the Neuro2a/APPswe Cell Model of AD

The Prenylflavonoid Xanthohumol Reduces Alzheimer-Like Changes and Modulates Multiple Pathogenic Molecular Pathways in the Neuro2a/APPswe Cell Model of AD

Identification of New Targets and the Virtual Screening of Lignans against Alzheimer’s Disease

Structural dynamics at the active site of the cancer‐associated flavoenzyme NQO1 probed by chemical modification with PMSF

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