Naringenin Upregulates AMPK-Mediated Autophagy to Rescue Neuronal Cells From β-Amyloid (1-42) Evoked Neurotoxicity.

Publisher: Humana Press Country of Publication: United States NLM ID: 8900963 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-1182 (Electronic) Linking ISSN: 08937648 NLM ISO Abbreviation: Mol Neurobiol Subsets: MEDLINE

Original Publication: Clifton, NJ : Humana Press, c1987-

AMP-Activated Protein Kinases/*metabolism ; Alzheimer Disease/*metabolism ; Autophagy/*drug effects ; Flavanones/*pharmacology ; Neurons/*pathology; Amyloid beta-Peptides/metabolism ; Animals ; Apoptosis/drug effects ; Mice ; Neurons/metabolism ; Neuroprotective Agents/pharmacology ; Signal Transduction/drug effects

Deposition of an amyloid-β peptide is one of the first events in the pathophysiology of Alzheimer's disease (AD) and is clinically characterized by Aβ plaques, tau tangles, and behavioral impairments that lead to neuronal death. A substantial number of studies encourage targeting the skewness in the production and degradation of amyloid-β could be among the promising therapies in the disease. Neuronal autophagy has emerged for an essential role in the degradation of such toxic aggregate-prone proteins in various neurodegenerative diseases. We profiled a small library of common dietary compounds and identified those that can enhance autophagy in neuronal cells. Here we noted naringenin in silico exhibits a robust affinity with AMP-activated protein kinase (AMPK) and upregulated AMPK-mediated autophagy signaling in neurons. Naringenin can induce autophagy promoting proteins such as ULK1, Beclin1, ATG5, and ATG7 in Neuro2a cells and primary mouse neurons as well. The knockdown of AMPK by siRNA-AMPK was complemented by naringenin that restored transcript levels of AMPK. Further, naringenin can reduce the levels of Aβ at a nontoxic concentration from neuronal cells. Moreover, it maintained the mitochondrial membrane potential and resisted reactive oxygen species production, which led to the protection against Aβ 1-42 evoked neurotoxicity. This highlights the neuroprotective potential of naringenin that can be developed as an anti-amyloidogenic nutraceutical.

Risk reduction of cognitive decline and dementia: WHO guidelines. Geneva: World Health Organization; 2019. Licence: CC BY-NC-SA 3.0 IGO.
Leong YQ, Ng KY, Chye SM et al (2020) Mechanisms of action of amyloid-beta and its precursor protein in neuronal cell death. Metab Brain Dis 35:11–30. (PMID: 31811496)
Serrano-Pozo A, Frosch MP, Masliah E, Hyman BT (2011) Neuropathological alterations in Alzheimer's disease. Cold Spring Harb Perspect Med 1(1):a006189. (PMID: 222291163234452)
Panza F, Lozupone M, Logroscino G, Imbimbo BP (2019) A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol 15(2):73–88. (PMID: 30610216)
Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R et al (2014) Alzheimer’s Disease Cooperative Study Steering Committee, Solanezumab Study Group Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 23(370(4)):311–321.
Salloway S, Sperling R, Fox NC (2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 370(4):322–333. (PMID: 244508914159618)
Anguiano J, Garner TP, Mahalingam M, Das BC, Gavathiotis E, Cuervo AM (2013) Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives. Nat Chem Biol 9:374–382. (PMID: 235846763661710)
Anding AL, Baehrecke EH (2017) Cleaning house: selective autophagy of organelles. Dev Cell 41(1):10–22. (PMID: 283993945395098)
Boland B, Kumar A, Lee S, Platt FM, Wegiel J, Yu H, Nixon RA (2008) Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J Neurosci 28(27):6926–6937. (PMID: 185961672676733)
Chen Y, Xu S, Wang N, Peng P, Yu Y, Zhang L, Ying Z, Wang H (2019) Dynasore suppresses mTORC1 activity and induces autophagy to regulate the clearance of protein aggregates in neurodegenerative diseases. Neurotox Res 36:108–116. (PMID: 30924108)
Ntsapi C, Lumkwana D, Swart C, du Toit A, Loos B (2018) New insights into autophagy dysfunction related to amyloid beta toxicity and neuropathology in Alzheimer’s disease. Int Rev Cell Mol Biol 336:321–361. (PMID: 29413893)
Vingtdeux V, Chandakkar P, Zhao H, d'Abramo C, Davies P, Marambaud P (2011) Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-beta peptide degradation. FASEB J 25:219–231. (PMID: 208520623005419)
Salminen A, Kaarniranta K, Haapasalo A, Soininen H, Hiltunen M (2011) AMP-activated protein kinase: a potential player in Alzheimer’s disease. J Neurochem 118:460–474. (PMID: 21623793)
Park SY, Lee HR, Lee WS, Shin HK, Kim HY, Hong KW (2016) Cilostazol modulates autophagic degradation of beta-amyloid peptide via SIRT1-coupled LKB1/AMPK alpha signaling in neuronal cells. PLoS One 11:e0160620. (PMID: 274947114975437)
Wu Y, Li X, Zhu JX, Xie W, Le W, Fan Z (2011) Resveratrol-activated AMPK/SIRT1/autophagy in cellular models of Parkinson’s disease. Neuro-Signals. 19:163–174. (PMID: 217786913699815)
Walter C, Clemens LE, Muller AJ, Fallier-Becker P, Proikas-Cezanne T, Riess O (2016) Activation of AMPK-induced autophagy ameliorates Huntington disease pathology in vitro. Neuropharmacology. 108:24–38. (PMID: 27133377)
Heras-Sandoval D, Perez-Rojas JM, Pedraza-Chaverri J (2020) Novel compounds for the modulation of mTOR and autophagy to treat neurodegenerative diseases. Cell Signal 65:109442. (PMID: 31639492)
Vingtdeux V, Giliberto L, Zhao H, Chandakkar P, Wu Q, Simon JE, Janle EM, Lobo J et al (2010) AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-b peptide metabolism. J Biol Chem 285:9100–9113.
Zobeiri M, Belwal T, Parvizi F, Naseri R, Farzaei MH, Nabavi SF, Sureda A, Nabavi SM (2018) Naringenin and its nano-formulations for fatty liver: Cellular modes of action and clinical perspective. Curr Pharm Biotechnol 19:196–205. (PMID: 29766801)
Salehi B, Fokou PVT, Sharifi-Rad M, Zucca P, Pezzani R, Martins N, Sharifi-Rad J (2019) The therapeutic potential of Naringenin: a review of clinical trials. Pharmaceuticals (Basel) 12(1):E11.
Youdim KA, Qaiser MZ, Begley DJ, Rice-Evans CA, Abbott NJ (2004) Flavonoid permeability across an in-situ model of the blood–brain barrier. Free Radic Biol Med 36:592–604. (PMID: 14980703)
Wang Q, Yang J, Zhang XM, Zhou L, Liao XL, Yang B (2015) Practical synthesis of naringenin. J Chem Res 39:455–457.
Wang GQ, Zhang B, He XM, Li DD, Shi JS, Zhang F (2019) Naringenin targets on astroglial Nrf2 to support dopaminergic neurons. Pharmacol Res 139:452–459. (PMID: 30527894)
Hegazy HG, Ali EHA, Sabry HA (2016) The neuroprotective action of naringenin on oseltamivir (Tamiflu) treated male rats. J Basic Appl Zool 77:83–90.
Khan MB, Khan MM, Khan A, Ahmed ME, Ishrat T, Tabassum R, Vaibhav K, Islam F (2012) Naringenin ameliorates Alzheimer’s disease (AD)-type neurodegeneration with cognitive impairment (AD-TNDCI) caused by the intracerebroventricular-streptozotocin in rat model. Neurochem Int 61(7):1081–1093. (PMID: 22898296)
Chen C, Wei YZ, He XM, Li DD, Wang GQ, Li JJ, Zhang F (2019) Naringenin produces neuroprotection against LPS-induced dopamine neurotoxicity via the inhibition of microglial NLRP3 inflammasome activation. Front Immunol 10:936. (PMID: 311189336504827)
Yang Z, Kuboyama T, Tohda C (2019) Naringenin promotes microglial M2 polarization and Aβ degradation enzyme expression. Phytother Res 33(4):1114–1121. (PMID: 30768735)
Siddiqi FH, Menzies FM, Lopez A et al (2019) Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing. Nat Commun 10:1817. (PMID: 310007206472390)
Dar NJ, Satti NK, Dutt P et al (2018) Attenuation of glutamate-induced Excitotoxicity by Withanolide-a in neuron-like cells: Role for PI3K/Akt/MAPK signaling pathway. Mol Neurobiol 55:2725–2739. (PMID: 28447311)
Gupta M, Wani A, Ahsan AU, Chopra M, Vishwakarma RA, Singh G, Kumar A (2018) Soluble Aβ 1-42 suppresses TNF-α and activates NLRP3 inflammasome in THP-1 macrophages. Cytokine. 111:84–87. (PMID: 30125779)
Klionsky DJ, Abdelmohsen K, Abe A et al (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3 ^rd edition). Autophagy. 12(1):1–222. (PMID: 267996524835977)
Gupta S, Ahsan AU, Wani A, Khajuria V, Nazir LA, Sharma S, Bhagat A, Sharma PR et al (2018) The amino analogue of β-boswellic acid efficiently attenuates the release of pro-inflammatory mediators than its parent compound through the suppression of NF-κB/IκBα signalling axis. Cytokine. 107:93–104.
Wani A, Gupta M, Ahmad M, Shah AM, Ahsan AU, Qazi PH, Malik F, Singh G et al (2019) Alborixin clears amyloid-β by inducing autophagy through PTEN-mediated inhibition of the AKT pathway. Autophagy. 15(10):1810–1828.
Perry SW, Norman JP, Barbieri J, Brown EB, Gelbard HA (2011) Mitochondrial membrane potential probes and the proton gradient: A practical usage guide. Biotechniques. 50(2):98–115. (PMID: 214862513115691)
Kaushal S, Ahsan AU, Sharma VL, Chopra M (2019) Epigallocatechin gallate attenuates arsenic induced genotoxicity via regulation of oxidative stress in balb/C mice. Mol Biol Rep 46:5355–5369. (PMID: 31350662)
Tanida I, Ueno T, Kominami E (2008) LC3 and Autophagy. Methods in Molecular Biology (Clifton, N.J.). 445:77-88.
Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132–141. (PMID: 212583673987946)
Tan CC, Yu JT, Tan MS, Jiang T, Zhu XC, Tan L (2014) Autophagy in aging and neurodegenerative diseases: Implications for pathogenesis and therapy. Neurobiol Aging 35:941–957. (PMID: 24360503)
Cai Z, Zhao B, Li K, Zhang L, Li C, Quazi SH, Tan Y (2012) Mammalian target of rapamycin: a valid therapeutic target through the autophagy pathway for Alzheimer’s disease? J Neurosci Res 90(6):1105–1118. (PMID: 22344941)
Nixon RA (2013) The role of autophagy in neurodegenerative disease. Nat Med 19:983–997. (PMID: 23921753)
Galluzzi L, Bravo-San Pedro JM, Levine B, Green DR, Kroemer G (2017) Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov 16(7):487–511. (PMID: 285293165713640)
Maher P, Dargusch R, Ehren JL, Okada S, Sharma K, Schubert D (2011) Fisetin lowers methylglyoxal dependent protein glycation and limits the complications of diabetes. PLoS One 6:e21226. (PMID: 217386233124487)
Saenz J, Santa-María C, Reyes-Quiroz ME et al (2018) Grapefruit flavonoid Naringenin regulates the expression of LXRα in THP-1 macrophages by modulating AMP-activated protein kinase. Mol Pharm 15(5):1735–1745. (PMID: 29140707)
Li S, Zhang Y, Sun Y et al (2019) Naringenin improves insulin sensitivity in gestational diabetes mellitus mice through AMPK. Nutr Diabetes 9:28. (PMID: 315913916779739)
Wu L, Lin C, Lin H et al (2016) Naringenin suppresses neuroinflammatory responses through inducing suppressor of cytokine signaling 3 expression. Mol Neurobiol 53:1080–1091. (PMID: 25579382)
Hale AN, Ledbetter DJ, Gawriluk TR, Rucker EB (2013) Autophagy: regulation and role in development. Autophagy. 9(7):951–972. (PMID: 241215963722331)
Nikoletopoulou V, Tavernarakis N (2018) Regulation and roles of autophagy at synapses. Trends Cell Biol 28:8.
Pickford F, Masliah E, Britschgi M, Lucin K, Narasimhan R, Jaeger PA, Small S, Spencer B et al (2008) The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates β-amyloid accumulation in mice. J Clin Invest 118(6):2190–2199.
Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, Füllgrabe J, Jackson A et al (2017) Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron. 93:1015–1034.
Cheignon C, Tomas M, Bonnefont-Rousselot D, Faller P, Hureau C, Collin F (2018) Oxidative stress and the β-amyloid peptide in Alzheimer’s disease. Redox Biol 14:450–464. (PMID: 29080524)
Kapogiannis D, Mattson MP (2011) Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease. Lancet Neurol 10:187–198. (PMID: 21147038)
Lou H, Jing X, Wei X, Shi H, Ren D, Zhang X (2014) Naringenin protects against 6-OHDA-induced neurotoxicity via activation of the Nrf2/ARE signaling pathway. Neuropharmacology. 79:380–388. (PMID: 24333330)

UGC/2016 University Grants Commission

Keywords: AICAR; AMPK; Aβ; GFAP; LC3B; MAP 2; Naringenin; ULK1; mTOR

0 (Amyloid beta-Peptides)
0 (Flavanones)
0 (Neuroprotective Agents)
EC 2.7.11.31 (AMP-Activated Protein Kinases)
HN5425SBF2 (naringenin)

Date Created: 20200617 Date Completed: 20210607 Latest Revision: 20220724

20221213

10.1007/s12035-020-01969-4

32542594