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Review
. 2020 Sep 11:8:42.
doi: 10.1186/s40364-020-00218-z. eCollection 2020.

Redox signaling and Alzheimer's disease: from pathomechanism insights to biomarker discovery and therapy strategy

Yuan-Yuan Chen #  1 , Min-Chang Wang #  2 , Yan-Ni Wang  1 , He-He Hu  1 , Qing-Quan Liu  3 , Hai-Jing Liu  4 , Ying-Yong Zhao  1
Affiliations
Review

Redox signaling and Alzheimer's disease: from pathomechanism insights to biomarker discovery and therapy strategy

Yuan-Yuan Chen et al. Biomark Res. .

Abstract

Abstract: Aging and average life expectancy have been increasing at a rapid rate, while there is an exponential risk to suffer from brain-related frailties and neurodegenerative diseases as the population ages. Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide with a projected expectation to blossom into the major challenge in elders and the cases are forecasted to increase about 3-fold in the next 40 years. Considering the etiological factors of AD are too complex to be completely understood, there is almost no effective cure to date, suggesting deeper pathomechanism insights are urgently needed. Metabolites are able to reflect the dynamic processes that are in progress or have happened, and metabolomic may therefore provide a more cost-effective and productive route to disease intervention, especially in the arena for pathomechanism exploration and new biomarker identification. In this review, we primarily focused on how redox signaling was involved in AD-related pathologies and the association between redox signaling and altered metabolic pathways. Moreover, we also expatiated the main redox signaling-associated mechanisms and their cross-talk that may be amenable to mechanism-based therapies. Five natural products with promising efficacy on AD inhibition and the benefit of AD intervention on its complications were highlighted as well.

Keywords: Alzheimer’s disease; Inflammation; Metabolomics; Neurodegenerative disease; Oxidative stress.

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Conflict of interest statement

Competing interestsThe authors declare that they have no conflicts of interest.

Figures

Fig. 1
Fig. 1
The primary oxidative stress-associated metabolic pathways in AD. AD is a neurodegenerative disease with a projected expectation to blossom into the major challenge in aging populations, while there is a severe paucity of both diagnosis and treatment for this disease. A series of metabolites with relevance to oxidative stress, including glucose metabolism, lipid metabolism, purine metabolism, tryptophan metabolism, vitamin metabolism and metal ion metabolism, have been major risk factors for AD progression, the intervention of which may provide novel insight into the development of mechanism-based therapies. AA: Anthranilic acid; F6P: fructose 6-phosphate; G3P: glyceraldehyde 3-phosphate; G6P: glucose 6-phosphate; GMP: guanosine-5′-monophosphate; 3-HAA: 3-hydroxyanthranilic acid; 3-HK: 3-hydroxykynurenine; KA: Kynurenic acid; PUFAs: polyunsaturated fatty acids; R5P: ribulose 5-phosphate
Fig. 2
Fig. 2
The main redox signaling-associated mechanisms and their cross-talk in AD progression. NOX, TGF-β, NF-κB and Nrf2 are remarkable mediators of oxidative stress that implicated in AD development. NOX is dedicated contributor Aβ-induced ROS generation, and NOX signaling pathway is closely associated with Aβ deposition and cognitive deficits. TGF-β/Smad signaling also promotes ROS production, and NOX4 is the main cause of TGF-β induced ROS generation via TGF-β/Smad/ROS signaling cascade. In addition, tau protein hyperphosphorylation is another hallmark of AD, which could deteriorate AD through TGF-β/Smad/NOX4/ERK1/2/tau protein cascade. Moreover, metal ions and NF–κB also contributes to AD progression by accelerating ROS and inflammation respectively, while Nrf2 shows potential protective effect against AD via promoting anti-oxidant responses and inhibiting NF–κB. Maxacalcitol is a vitamin D analogue that significantly alleviates cognitive impairment of AD rats through elevating Nrf2, restraining inflammation and reducing the hyperphosphorylation of tau proteins. ERK: extracellular signal-related kinase; GCLM: glutamate-cysteine ligase modifier subunit; HO-1: haem oxygenase-1; Keap1: Kelch-like ECH-associted protein 1; MEK: mitogen-activated protein kinase/extracellular signal-related kinase; NQO1: NAD(P)H dehydrogenase quinone 1, SARA: smad anchor for receptor activation
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References

    1. Nakamura A, Kaneko N, Villemagne VL, et al. High performance plasma amyloid-β biomarkers for Alzheimer's disease. Nature. 2018;554(7691):249–254. - PubMed
    1. Group GBDNDC Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the global burden of disease study 2015. Lancet Neurol. 2017;16(11):877–897. - PMC - PubMed
    1. Cuperlovic-Culf M, Badhwar A. Recent advances from metabolomics and lipidomics application in Alzheimer's disease inspiring drug discovery. Expert Opin Drug Discov. 2020;15(3):319–331. - PubMed
    1. Li T, Braunstein KE, Zhang J, et al. The neuritic plaque facilitates pathological conversion of tau in an Alzheimer's disease mouse model. Nat Commun. 2016;7:12082. - PMC - PubMed
    1. Qiang W, Yau WM, Lu JX, et al. Structural variation in amyloid-β fibrils from Alzheimer's disease clinical subtypes. Nature. 2017;541(7636):217–221. - PMC - PubMed

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