Myricetin protected against Aβ oligomer-induced synaptic impairment, mitochondrial function and oxidative stress in SH-SY5Y cells via ERK1/2/GSK-3β pathways

Alzheimer’s disease is characterized by abnormal β-amyloid (Aβ) plaque accumulation, tau hyperphosphorylation, reactive oxidative stress, mitochondrial dysfunction and synaptic loss. Myricetin, a dietary flavonoid, has been shown to have neuroprotective effects in vitro and in vivo. Here, we aimed to elucidate the mechanism and pathways involved in myricetin’s protective effect on the toxicity induced by the Aβ42 oligomer. Neuronal SH-SY5Y cells were pretreated with myricetin before incubation with Aβ42 oligomer. The levels of pre- and postsynaptic proteins, mitochondrial division and fusion proteins, glycogen synthase kinase-3 β (GSK-3β) and extracellular regulated kinase (ERK) 1/2 were assessed by Western blotting. Flow cytometry assays for mitochondrial membrane potential (JC1) and reactive oxidative stress, as well immunofluorescence staining for lipid peroxidation (4-HNE) and DNA oxidation (8-OHdG), were performed. We found that myricetin prevented Aβ42 oligomer-induced tau phosphorylation and the reduction in pre/postsynaptic proteins. In addition, myricetin reduced reactive oxygen species generation, lipid peroxidation, and DNA oxidation induced by the Aβ42 oligomer. Moreover, myricetin prevented the Aβ42 oligomer-induced reduction in mitochondrial fusion proteins (mitofusin-1, mitofusin-2), fission protein (dynamin-related protein 1) phosphorylation, and mitochondrial membrane potential via the associated GSK-3β and ERK 1/2 signaling pathways. In conclusion, this study provides new insight into the neuroprotective mechanism of myricetin against Aβ42 oligomer-induced toxicity.

[1]  L. Buée,et al.  Tau promotes oxidative stress-associated cycling neurons in S phase as a pro-survival mechanism: Possible implication for Alzheimer’s disease , 2022, Progress in Neurobiology.

[2]  S. Leurgans,et al.  Association of Dietary Intake of Flavonols With Changes in Global Cognition and Several Cognitive Abilities , 2022, Neurology.

[3]  R. Ni,et al.  ChemR23 signaling ameliorates cognitive impairments in diabetic mice via dampening oxidative stress and NLRP3 inflammasome activation , 2022, Redox biology.

[4]  J. Loor,et al.  Effect of Myricetin on Lipid Metabolism in Primary Calf Hepatocytes Challenged with Long-Chain Fatty Acids , 2022, Metabolites.

[5]  R. Ni,et al.  Quercetin reduces APP expression, oxidative stress and mitochondrial dysfunction in the N2a/APPswe cells via ERK1/2 and AKT pathways , 2022, bioRxiv.

[6]  H. Zu,et al.  DHCR24 Knockdown Induces Tau Hyperphosphorylation at Thr181, Ser199, Ser262, and Ser396 Sites via Activation of the Lipid Raft-Dependent Ras/MEK/ERK Signaling Pathway in C8D1A Astrocytes , 2022, Molecular Neurobiology.

[7]  N. Acharya,et al.  Design and optimization of myricetin encapsulated nanostructured lipid carriers: In-vivo assessment against cognitive impairment in amyloid beta (1-42) intoxicated rats. , 2022, Life sciences.

[8]  Shifeng Xiao,et al.  Myricetin Restores Aβ-Induced Mitochondrial Impairments in N2a-SW Cells. , 2022, ACS chemical neuroscience.

[9]  Keyvan Yousefi,et al.  The Role of ERK1/2 Pathway in the Pathophysiology of Alzheimer’s Disease: An Overview and Update on New Developments , 2022, Cellular and Molecular Neurobiology.

[10]  B. Viollet,et al.  Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy , 2019, bioRxiv.

[11]  H. Xiang,et al.  Pharmacological Actions of Myricetin in the Nervous System: A Comprehensive Review of Preclinical Studies in Animals and Cell Models , 2021, Frontiers in Pharmacology.

[12]  R. Pare,et al.  Tβ4 ameliorates oxidative damage and apoptosis through ERK/MAPK and 5-HT1A signaling pathway in Aβ insulted SH-SY5Y cells. , 2021, Life sciences.

[13]  R. Ni,et al.  Rapamycin attenuated zinc-induced tau phosphorylation and oxidative stress in animal model: Involvement of dual mTOR/p70S6K and Nrf2/HO-1 pathways , 2021, bioRxiv.

[14]  Ran Zhang,et al.  Flavonoids with Potential Anti-Amyloidogenic Effects as Therapeutic Drugs for Treating Alzheimer's Disease. , 2021, Journal of Alzheimer's disease : JAD.

[15]  Jie Chen,et al.  Myricetin slows liquid–liquid phase separation of Tau and activates ATG5-dependent autophagy to suppress Tau toxicity , 2021, The Journal of biological chemistry.

[16]  Liang Shen,et al.  Myricetin supplementation decreases hepatic lipid synthesis and inflammation by modulating gut microbiota. , 2021, Cell reports.

[17]  D. Teplow,et al.  Myricetin prevents high molecular weight Aβ1-42 oligomer-induced neurotoxicity through antioxidant effects in cell membranes and mitochondria. , 2021, Free radical biology & medicine.

[18]  Andrew J Want,et al.  Candidate Alzheimer’s Disease Biomarker miR-483-5p Lowers TAU Phosphorylation by Direct ERK1/2 Repression , 2021, International journal of molecular sciences.

[19]  Derek H. Oakley,et al.  Targeting Tau Mitigates Mitochondrial Fragmentation and Oxidative Stress in Amyotrophic Lateral Sclerosis , 2021, Molecular Neurobiology.

[20]  Jong-Seok Moon,et al.  NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer's diseases , 2021, Redox biology.

[21]  R. Pluta,et al.  Myricetin as a Promising Molecule for the Treatment of Post-Ischemic Brain Neurodegeneration , 2021, Nutrients.

[22]  Jun Luo,et al.  Mangiferin prevents the impairment of mitochondrial dynamics and an increase in oxidative stress caused by excessive fluoride in SH‐SY5Y cells , 2021, Journal of biochemical and molecular toxicology.

[23]  Yizhuo Wang,et al.  Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance , 2021, Theranostics.

[24]  J. Pei,et al.  Myricetin: A review of the most recent research. , 2020, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[25]  Zihui Xu,et al.  Quercetin-3-O-Glucuronide Alleviates Cognitive Deficit and Toxicity in Aβ1-42 -Induced AD-Like Mice and SH-SY5Y Cells. , 2020, Molecular nutrition & food research.

[26]  Yue Liu,et al.  Sulforaphene Ameliorates Neuroinflammation and Hyperphosphorylated Tau Protein via Regulating the PI3K/Akt/GSK-3β Pathway in Experimental Models of Alzheimer's Disease , 2020, Oxidative medicine and cellular longevity.

[27]  B. Hyman,et al.  Synergy between amyloid-β and tau in Alzheimer’s disease , 2020, Nature Neuroscience.

[28]  D. Praticò,et al.  Glycogen synthase kinase-3 signaling in Alzheimer's disease. , 2020, Biochimica et biophysica acta. Molecular cell research.

[29]  S. Leurgans,et al.  Dietary flavonols and risk of Alzheimer dementia , 2020, Neurology.

[30]  M. Rehman,et al.  Myricetin Abrogates Cisplatin-Induced Oxidative Stress, Inflammatory Response, and Goblet Cell Disintegration in Colon of Wistar Rats , 2019, Plants.

[31]  Zengjie Zhang,et al.  Activation of Nrf2/HO-1 signal with Myricetin for attenuating ECM degradation in human chondrocytes and ameliorating the murine osteoarthritis. , 2019, International immunopharmacology.

[32]  K. Blennow,et al.  Identification of neurotoxic cross-linked amyloid-β dimers in the Alzheimer's brain. , 2019, Brain : a journal of neurology.

[33]  A. Alexiou,et al.  Role of GTPases in the Regulation of Mitochondrial Dynamics in Alzheimer’s Disease and CNS-Related Disorders , 2018, Molecular Neurobiology.

[34]  Sun-Young Park,et al.  Enhancing effects of myricetin on the osteogenic differentiation of human periodontal ligament stem cells via BMP‐2/Smad and ERK/JNK/p38 mitogen‐activated protein kinase signaling pathway , 2018, European journal of pharmacology.

[35]  Ying Liu,et al.  Dihydromyricetin inhibits microglial activation and neuroinflammation by suppressing NLRP3 inflammasome activation in APP/PS1 transgenic mice , 2018, CNS neuroscience & therapeutics.

[36]  C. Humpel,et al.  Differential Hyperphosphorylation of Tau-S199, -T231 and -S396 in Organotypic Brain Slices of Alzheimer Mice. A Model to Study Early Tau Hyperphosphorylation Using Okadaic Acid , 2018, Front. Aging Neurosci..

[37]  P. Reddy,et al.  Hippocampal mutant APP and amyloid beta-induced cognitive decline, dendritic spine loss, defective autophagy, mitophagy and mitochondrial abnormalities in a mouse model of Alzheimer’s disease , 2018, Human molecular genetics.

[38]  Wenzhang Wang,et al.  Mfn2 ablation causes an oxidative stress response and eventual neuronal death in the hippocampus and cortex , 2018, Molecular Neurodegeneration.

[39]  R. Chang,et al.  A reciprocal relationship between reactive oxygen species and mitochondrial dynamics in neurodegeneration , 2017, Redox biology.

[40]  P. Reddy,et al.  Hippocampal phosphorylated tau induced cognitive decline, dendritic spine loss and mitochondrial abnormalities in a mouse model of Alzheimer’s disease , 2018, Human molecular genetics.

[41]  A. Palmeri,et al.  LTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent , 2017, eLife.

[42]  Y. Lim,et al.  Flavones with inhibitory effects on glycogen synthase kinase 3β , 2017, Applied Biological Chemistry.

[43]  F. Khodagholi,et al.  Myricetin protects hippocampal CA3 pyramidal neurons and improves learning and memory impairments in rats with Alzheimer's disease , 2016, Neural regeneration research.

[44]  N. Soussi-Yanicostas,et al.  Tau Hyperphosphorylation and Oxidative Stress, a Critical Vicious Circle in Neurodegenerative Tauopathies? , 2015, Oxidative medicine and cellular longevity.

[45]  V. de Freitas,et al.  Effect of Myricetin, Pyrogallol, and Phloroglucinol on Yeast Resistance to Oxidative Stress , 2015, Oxidative medicine and cellular longevity.

[46]  H. Nishijo,et al.  Phenolic compounds prevent beta-amyloid-protein oligomerization and synaptic dysfunction by site-specific binding , 2012, Alzheimer's & Dementia.

[47]  B. Strooper,et al.  The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes , 2012, Nature Neuroscience.

[48]  Sanjay Kumar,et al.  Conformational transition in the substrate binding domain of β-secretase exploited by NMA and its implication in inhibitor recognition: BACE1–myricetin a case study , 2011, Neurochemistry International.

[49]  R. Castellani,et al.  Alzheimer disease. , 2010, Disease-a-month : DM.

[50]  A. Murase,et al.  Phenolic compounds prevent Alzheimer's pathology through different effects on the amyloid-beta aggregation pathway. , 2009, The American journal of pathology.

[51]  Z. Khachaturian.  Alzheimer's & Dementia: The Journal of the Alzheimer's Association , 2008, Alzheimer's & Dementia.

[52]  Shaomin Li,et al.  Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory , 2008, Nature Medicine.

[53]  T. Kihara,et al.  Multifunction of myricetin on A beta: neuroprotection via a conformational change of A beta and reduction of A beta via the interference of secretases. , 2008, Journal of neuroscience research.

[54]  Toshihiko Oka,et al.  Mitotic Phosphorylation of Dynamin-related GTPase Drp1 Participates in Mitochondrial Fission* , 2007, Journal of Biological Chemistry.

[55]  K. Leroy,et al.  Increased level of active GSK‐3β in Alzheimer’s disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration , 2007, Neuropathology and applied neurobiology.