Dieckol Ameliorates Aβ Production via PI3K/Akt/GSK-3β Regulated APP Processing in SweAPP N2a Cell
Abstract
:1. Introduction
2. Results and Discussion
2.1. Effects of Phlorotannins on Cell Viability
2.2. Inhibitory Effects of Phlorotannins on Aβ Production
2.3. Effects of Phlorotannins on APP Proteolytic Enzymes Expression and Activity
2.4. Regulation of Aβ Production by PI3K/Akt/GSK-3β Signaling Pathway
3. Materials and Methods
3.1. Cell Culture
3.2. Cell Viability
3.3. Aβ ELISA Analysis
3.4. Western Blotting Assay
3.5. Statistical Analysis
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
- Eimer, W.A.; Vassar, R. Neuron Loss in the 5XFAD mouse model of Alzheimer’s Disease correlates with intraneuronal Aβ42 accumulation and caspase-3 activation. Mol. Neurodegener. 2013, 8, 2. [Google Scholar] [CrossRef] [Green Version]
- Tu, S.; Okamoto, S.; Lipton, S.A.; Xu, H. Oligomeric Aβ-induced synaptic dysfunction in Alzheimer’s disease. Mol. Neurodegener. 2014, 9, 48. [Google Scholar] [CrossRef] [Green Version]
- Cabezas-Opazo, F.A.; Vergara-Pulgar, K.; Pérez, M.J.; Jara, C.; Osorio-Fuentealba, C.; Quintanilla, R.A. Mitochondrial dysfunction contributes to the pathogenesis of Alzheimer’s disease. Oxid. Med. Cell Longev. 2015, 2015, 509654. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Minter, M.R.; Taylor, J.M.; Crack, P.J. The Contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease. J. Neurochem. 2016, 136, 457–474. [Google Scholar] [CrossRef] [PubMed]
- Govoni, S.; Mura, E.; Racchi, M.; Lanni, C.; Grilli, M.; Zappettini, S.; Salamone, A.; Olivero, G.; Pittaluga, A.; Marchi, M. Dangerous liaisons between beta-amyloid and cholinergic neurotransmission. Curr. Pharm. Des. 2014, 20, 2525–2538. [Google Scholar] [CrossRef]
- Li, Y.; Zhou, W.; Tong, Y.; He, G.; Song, W. Control of APP Processing and Aβ generation level by BACE1 enzymatic activity and transcription. FASEB J. 2006, 20, 285–292. [Google Scholar] [CrossRef]
- Ohno, M.; Sametsky, E.A.; Younkin, L.H.; Oakley, H.; Younkin, S.G.; Citron, M.; Vassar, R.; Disterhoft, J.F. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron 2004, 41, 27–33. [Google Scholar] [CrossRef] [Green Version]
- Ring, S.; Weyer, S.W.; Kilian, S.B.; Waldron, E.; Pietrzik, C.U.; Filippov, M.A.; Herms, J.; Buchholz, C.; Eckman, C.B.; Korte, M.; et al. The secreted β-amyloid precursor protein ectodomain APPsα is sufficient to rescue the anatomical, behavioral and electrophysiological abnormalities of APP-deficient mice. J. Neurosci. 2007, 27, 7817–7826. [Google Scholar] [CrossRef]
- Yang, J.; Chen, L.; Yang, J.; Ding, J.; Rong, H.; Dong, W.; Li, X. High mobility group box-1 induces migration of vascular smooth muscle cells via TLR4-dependent PI3K/Akt pathway activation. Mol. Biol. Rep. 2012, 39, 3361–3367. [Google Scholar] [CrossRef]
- Tang, Y.; Liu, P.; Tian, Y.; Xu, Y.; Ren, F.; Cui, X.; Fan, J. Overexpression of ribonuclease inhibitor defines good prognosis and suppresses proliferation and metastasis in human colorectal cancer cells via PI3K/AKT pathway. Clin. Transl. Oncol. 2015, 17, 306–313. [Google Scholar] [CrossRef] [PubMed]
- Martín, D.; Salinas, M.; López-Valdaliso, R.; Serrano, E.; Recuero, M.; Cuadrado, A. Effect of the Alzheimer amyloid fragment Aβ(25–35) on Akt/PKB kinase and survival of PC12 cells. J. Neurochem. 2001, 78, 1000–1008. [Google Scholar] [CrossRef] [PubMed]
- Liu, S.J.; Zhang, A.H.; Li, H.L.; Wang, Q.; Deng, H.M.; Netzer, W.J.; Xu, H.; Wang, J.Z. Overactivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory. J. Neurochem. 2003, 87, 1333–1344. [Google Scholar] [CrossRef]
- Beurel, E.; Grieco, S.F.; Jope, R.S. Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases. Pharmacol. Ther. 2015, 148, 114–131. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hurtado, D.E.; Molina-Porcel, L.; Carroll, J.C.; MacDonald, C.; Aboagye, A.K.; Trojanowski, J.Q.; Lee, V.M. Selectively Silencing GSK-3 Isoforms reduces plaques and tangles in mouse models of Alzheimer’s disease. J. Neurosci. 2012, 32, 7392–7402. [Google Scholar] [CrossRef] [Green Version]
- Cho, J.H.; Johnson, G.V. Glycogen synthase kinase 3β induces caspase-cleaved tau aggregation in situ. J. Biol. Chem. 2004, 279, 54716–54723. [Google Scholar] [CrossRef] [Green Version]
- DaRocha-Souto, B.; Coma, M.; Perez-Nievas, B.G.; Scotton, T.C.; Siao, M.; Sánchez-Ferrer, P.; Hashimoto, T.; Fan, Z.; Hudry, E.; Barroeta, I.; et al. Activation of Glycogen synthase kinase-3 beta mediates β-amyloid induced neuritic damage in Alzheimer’s disease. Neurobiol. Dis. 2012, 45, 425–437. [Google Scholar] [CrossRef] [Green Version]
- Ly, P.T.; Wu, Y.; Zou, H.; Wang, R.; Zhou, W.; Kinoshita, A.; Zhang, M.; Yang, Y.; Cai, F.; Woodgett, J.; et al. Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J. Clin. Investig. 2013, 123, 224–235. [Google Scholar] [CrossRef] [Green Version]
- Takashima, A.; Noguchi, K.; Michel, G.; Mercken, M.; Hoshi, M.; Ishiguro, K.; Imahori, K. Exposure of rat hippocampal neurons to amyloid Β peptide (25–35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3β. Neurosci. Lett. 1996, 203, 33–36. [Google Scholar] [CrossRef]
- Reddy, P.H. Amyloid beta-induced glycogen synthase kinase 3β phosphorylated VDAC1 in Alzheimer’s disease: Implications for synaptic dysfunction and neuronal damage. Biochim. Biophys. Acta 2013, 1832, 1913–1921. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kim, A.R.; Shin, T.S.; Lee, M.S.; Park, J.Y.; Park, K.E.; Yoon, N.Y.; Kim, J.S.; Choi, J.S.; Jang, B.C.; Byun, D.S.; et al. Isolation and identification of phlorotannins from Ecklonia Stolonifera with antioxidant and anti-inflammatory properties. J. Agric. Food Chem. 2009, 57, 3483–3489. [Google Scholar] [CrossRef]
- Kim, E.K.; Tang, Y.; Kim, Y.S.; Hwang, J.W.; Choi, E.J.; Lee, J.H.; Lee, S.H.; Jeon, Y.J.; Park, P.J. First evidence that Ecklonia Cava-derived dieckol attenuates MCF-7 human breast carcinoma cell migration. Mar. Drugs 2015, 13, 1785–1797. [Google Scholar] [CrossRef] [Green Version]
- Kim, H.; Kong, C.S.; Lee, J.I.; Kim, H.; Baek, S.; Seo, Y. Evaluation of inhibitory effect of phlorotannins from Ecklonia Cava on triglyceride accumulation in adipocyte. J. Agric. Food Chem. 2013, 61, 8541–8547. [Google Scholar] [CrossRef] [PubMed]
- Kang, M.C.; Wijesinghe, W.A.J.P.; Lee, S.H.; Kang, S.M.; Ko, S.C.; Yang, X.; Kang, N.; Jeon, B.T.; Kim, J.; Lee, D.H.; et al. Dieckol isolated from brown seaweed Ecklonia Cava attenuates type ІІ diabetes in db/db mouse model. Food Chem. Toxicol. 2013, 53, 294–298. [Google Scholar] [CrossRef]
- Seong, S.H.; Paudel, P.; Jung, H.A.; Choi, J.S. Identifying phlorofucofuroeckol-A as a dual inhibitor of amyloid-β25-35 self-aggregation and insulin glycation: Elucidation of the molecular mechanism of action. Mar. Drugs 2019, 17, 600. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, J.; Jun, M. Dual BACE1 and cholinesterase inhibitory effects of phlorotannins from Ecklonia cava-an in vitro and in silico study. Mar. Drugs 2018, 17, 91. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, S.; Youn, K.; Kim, D.H.; Ahn, M.R.; Yoon, E.; Kim, O.Y.; Jun, M. Anti-neuroinflammatory property of phlorotannins from Ecklonia cava on Aβ25–35-induced damage in PC12 cells. Mar. Drugs 2018, 17, 7. [Google Scholar] [CrossRef] [Green Version]
- Vassar, R.; Bennett, B.D.; Babu-Khan, S.; Kahn, S.; Mendiaz, E.A.; Denis, P.; Teplow, D.B.; Ross, S.; Amarante, P.; Loeloff, R. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999, 286, 735–741. [Google Scholar] [CrossRef] [Green Version]
- Jang, J.K.; Park, K.J.; Lee, J.H.; Ko, K.Y.; Kang, S.; Kim, I.Y. Selenoprotein S is required for clearance of C99 through endoplasmic reticulum-associated degradation. Biochem. Biophys. Res. Commun. 2017, 486, 444–450. [Google Scholar] [CrossRef]
- Toh, W.H.; Tan, J.Z.A.; Zulkefli, K.L.; Houghton, F.J.; Gleeson, P.A. Amyloid precursor protein traffics from the golgi directly to early endosomes in an Arl5b-and AP4-dependent pathway. Traffic 2017, 18, 159–175. [Google Scholar] [CrossRef]
- Furusawa, K.; Takasugi, T.; Chiu, Y.W.; Hori, Y.; Tomita, T.; Fukuda, M.; Hisanaga, S.I. CD2-Associated protein (CD2AP) overexpression accelerates amyloid precursor protein (APP) transfer from early endosomes to the lysosomal degradation pathway. J. Biol. Chem. 2019, 294, 10886–10899. [Google Scholar] [CrossRef]
- Kuperstein, I.; Broersen, K.; Benilova, I.; Rozenski, J.; Jonckheere, W.; Debulpaep, M.; Vandersteen, A.; Segers-Nolten, I.; Van Der Werf, K.; Subramaniam, V. Neurotoxicity of lzheimer’s disease Aβ peptides is induced by small changes in the Aβ42 to Aβ40 ratio. EMBO J. 2010, 29, 3408–3420. [Google Scholar] [CrossRef] [PubMed]
- Pauwels, K.; Williams, T.L.; Morris, K.L.; Jonckheere, W.; Vandersteen, A.; Kelly, G.; Schymkowitz, J.; Rousseau, F.; Pastore, A.; Serpell, L.C.; et al. Structural basis or increased toxicity of pathological aβ42:aβ40 ratios in Alzheimer Disease. J. Biol. Chem. 2012, 287, 5650–5660. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Roche, J.; Shen, Y.; Lee, J.H.; Ying, J.; Bax, A. Monomeric Aβ1–40 and Aβ1–42 peptides in solution adopt very similar ramachandran map distributions that closely resemble random coil. Biochemistry 2016, 55, 762–775. [Google Scholar] [CrossRef] [Green Version]
- Selkoe, D.J.; Schenk, D. Alzheimer’s disease: Molecular understanding predicts amyloid-based therapeutics. Annu. Rev. Pharmacol. Toxicol. 2003, 43, 545–584. [Google Scholar] [CrossRef]
- May, P.C.; Dean, R.A.; Lowe, S.L.; Martenyi, F.; Sheehan, S.M.; Boggs, L.N.; Monk, S.A.; Mathes, B.M.; Mergott, D.J.; Watson, B.M.; et al. Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-secretase inhibitor. J. Neurosci. 2011, 31, 16507–16516. [Google Scholar] [CrossRef] [Green Version]
- Kang, I.J.; Jeon, Y.E.; Yin, X.F.; Nam, J.S.; You, S.G.; Hong, M.S.; Jang, B.G.; Kim, M. Butanol extract of Ecklonia Cava prevents production and aggregation of beta-amyloid and reduces beta-amyloid mediated neuronal death. Food Chem. Toxicol. 2011, 49, 2252–2259. [Google Scholar] [CrossRef]
- Kang, I.J.; Jang, B.G.; In, S.; Choi, B.; Kim, M.; Kim, M.J. Phlorotannin-Rich Ecklonia Cava Reduces the production of beta-amyloid by modulating alpha-and gamma-secretase expression and activity. Neurotoxicology 2013, 34, 16–24. [Google Scholar] [CrossRef]
- Chong, Z.Z.; Li, F.; Maiese, K. Oxidative Stress in the Brain: Novel Cellular Targets that Govern Survival during Neurodegenerative Disease. Prog. Neurobiol. 2005, 75, 207–246. [Google Scholar] [CrossRef]
- Tokutake, T.; Kasuga, K.; Yajima, R.; Sekine, Y.; Tezuka, T.; Nishizawa, M.; Ikeuchi, T. Hyperphosphorylation of Tau Induced by Naturally Secreted Amyloid-β at Nanomolar Concentrations is Modulated by Insulin-Dependent Akt-GSK3β Signaling Pathway. J. Biol. Chem. 2012, 287, 35222–35233. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Durairajan, S.S.K.; Liu, L.-F.; Lu, J.-H.; Chen, L.-L.; Yuan, Q.; Chung, S.K.; Huang, L.; Li, X.-S.; Huang, J.-D.; Li, M. Berberine ameliorates β-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer’s disease transgenic mouse model. Neurobiol. Aging 2012, 33, 2903–2919. [Google Scholar] [CrossRef] [PubMed]
- Wang, Z.; Huang, X.; Zhao, P.; Zhao, L.; Wang, Z. Catalpol Inhibits amyloid-β generation through promoting α-cleavage of APP in Swedish mutant APP overexpressed N2a Cells. Front. Aging Neurosci. 2018, 10, 66. [Google Scholar] [CrossRef] [PubMed]
- Liu, F.; Wang, Y.; Yan, M.; Zhang, L.; Pang, T.; Liao, H. Glimepiride attenuates Abeta production via suppressing BACE1 activity in cortical neurons. Neurosci. Lett. 2013, 557 Pt B, 90–94. [Google Scholar] [CrossRef]
- Paris, D.; Ganey, N.J.; Laporte, V.; Patel, N.S.; Beaulieu-Abdelahad, D.; Bachmeier, C.; March, A.; Ait-Ghezala, G.; Mullan, M.J. Reduction of β-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer’s disease. J. Neuroinflamm. 2010, 7, 17. [Google Scholar] [CrossRef] [Green Version]
- Wang, J.; Zheng, J.; Huang, C.; Zhao, J.; Lin, J.; Zhou, X.; Naman, C.B.; Wang, N.; Gerwick, W.H.; Wang, Q.; et al. Eckmaxol, a phlorotannin extracted from Ecklonia maxima, produces anti-β-amyloid oligomer neuroprotective effects possibly via directly acting on glycogen synthase kinase 3β. ACS Chem. Neurosci. 2018, 9, 1349–1356. [Google Scholar] [CrossRef]
- Lin, J.J.; Yu, J.; Zhao, J.Y.; Zhang, K.; Zheng, J.C.; Wang, J.L.; Huang, C.H.; Zhang, J.R.; Yan, X.J.; Gerwick, W.H.; et al. Fucoxanthin, a Marine Carotenoid, Attenuates beta-Amyloid Oligomer-Induced Neurotoxicity Possibly via Regulating the PI3K/Akt and the ERK Pathways in SH-SY5Y Cells. Oxid. Med. Cell. Longev. 2017, 2017, 6792543. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shen, Y.; Zhang, Q.; Gao, X.; Ding, F. An active fraction of Achyranthes Bidentata Polypeptides prevents apoptosis induced by serum deprivation in SH-SY5Y cells through activation of PI3K/AKT/Gsk3β pathways. Neurochem. Res. 2011, 36, 2186–2194. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.; Sui, H.; Zheng, Y.; Jiang, Y.; Shi, Y.; Liang, J.; Zhao, L. Curcumin-primed exosomes potently ameliorate cognitive function in AD mice by inhibiting hyperphosphorylation of the tau protein through the AKT/GSK-3β pathway. Nanoscale 2019, 11, 7481–7496. [Google Scholar] [CrossRef]
- Tao, J.; Cui, Y.; Duan, Y.; Zhang, N.; Wang, C.; Zhang, F. Puerarin Attenuates locomotor and cognitive deficits as well as hippocampal neuronal injury through the PI3K/Akt1/GSK-3β signaling pathway in an in vivo model of cerebral ischemia. Oncotarget 2017, 8, 106283–106295. [Google Scholar] [CrossRef] [Green Version]
- Wang, S.; He, B.; Hang, W.; Wu, N.; Xia, L.; Wang, X.; Zhang, Q.; Zhou, X.; Feng, Z.; Chen, Q. Berberine alleviates tau hyperphosphorylation and axonopathy-associated with diabetic encephalopathy via restoring PI3K/Akt/GSK3β pathway. J. Alzheimer’s Dis. 2018, 65, 1385–1400. [Google Scholar] [CrossRef]
- Kang, S.; Cha, S.; Ko, J.; Kang, M.; Kim, D.; Heo, S.; Kim, J.; Heu, M.; Kim, Y.; Jung, W.; et al. Neuroprotective effects of phlorotannins isolated from a brown alga, Ecklonia cava, against H2O2-induced oxidative stress in murine hippocampal HT22 cells. Environ. Toxicol. Pharmacol. 2012, 34, 96–105. [Google Scholar] [CrossRef]
- Cui, Y.; Park, J.; Wu, J.; Lee, J.; Yang, Y.; Kang, M.; Jung, S.; Park, J.; Yoo, E.; Kim, S.; et al. Dieckol Attenuates Microglia-mediated Neuronal Cell Death via ERK, Akt and NADPH Oxidase-mediated Pathways. Korean J. Physiol. Pharmacol. 2015, 19, 219–228. [Google Scholar] [CrossRef] [PubMed]
- Parihar, M.S.; Brewer, G.J. Amyloid-β as a modulator of synaptic plasticity. J. Alzheimer’s Dis. 2010, 22, 741–763. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cui, Y.; Amarsanaa, K.; Lee, J.H.; Rhim, J.K.; Kwon, J.M.; Kim, S.H.; Park, J.M.; Jung, S.C.; Eun, S.Y. Neuroprotective mechanisms of dieckol against glutamate toxicity through reactive oxygen species scavenging and nuclear factor-like 2/heme oxygenase-1 pathway. Korean J. Physiol. Pharmacol. 2019, 23, 121–130. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jung, H.; Oh, S.; Choi, J. Molecular docking studies of phlorotannins from Eisenia bicyclis with BACE1 inhibitory activity. Bioorg. Med. Chem. Lett. 2010, 20, 3211–3215. [Google Scholar] [CrossRef]
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Yoon, J.-H.; Lee, N.; Youn, K.; Jo, M.R.; Kim, H.-R.; Lee, D.-S.; Ho, C.-T.; Jun, M. Dieckol Ameliorates Aβ Production via PI3K/Akt/GSK-3β Regulated APP Processing in SweAPP N2a Cell. Mar. Drugs 2021, 19, 152. https://doi.org/10.3390/md19030152
Yoon J-H, Lee N, Youn K, Jo MR, Kim H-R, Lee D-S, Ho C-T, Jun M. Dieckol Ameliorates Aβ Production via PI3K/Akt/GSK-3β Regulated APP Processing in SweAPP N2a Cell. Marine Drugs. 2021; 19(3):152. https://doi.org/10.3390/md19030152
Chicago/Turabian StyleYoon, Jeong-Hyun, Nayoung Lee, Kumju Youn, Mi Ra Jo, Hyeung-Rak Kim, Dong-Seok Lee, Chi-Tang Ho, and Mira Jun. 2021. "Dieckol Ameliorates Aβ Production via PI3K/Akt/GSK-3β Regulated APP Processing in SweAPP N2a Cell" Marine Drugs 19, no. 3: 152. https://doi.org/10.3390/md19030152