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Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

Dihydroartemisinin Ameliorates Decreased Neuroplasticity-Associated Proteins and Excessive Neuronal Apoptosis in APP/PS1 Mice

Author(s): Yueyang Zhao, Zhimin Long, Yuanjie Liu, Min Luo, Yu Qiu, Nur F.B. Idris, Aijia Song, Kejian Wang* and Guiqiong He*

Volume 17 , Issue 10 , 2020

Page: [916 - 925] Pages: 10

DOI: 10.2174/1567205017666201215124746

Price: $65

Abstract

Background: Alzheimer's disease (AD) is one of the worst neurodegenerative disorders worldwide, with extracellular senile plaques (SP), subsequent intracellular neurofibrillary tangles (NFTs) and final neuron loss and synaptic dysfunction as the main pathological characteristics. Excessive apoptosis is the main cause of irreversible neuron loss. Thus, therapeutic intervention for these pathological features has been considered a promising strategy to treat or prevent AD. Dihydroartemisin (DHA) is a widely used first-line drug for malaria. Our previous study showed that DHA treatment significantly accelerated Aβ clearance, improved memory and cognitive deficits in vivo and restored autophagic flux both in vivo and in vitro.

Methods: The present study intended to explore the neuroprotective effect of DHA on neuron loss in APP/PS1 double-transgenic mice and the underlying mechanisms involved. Transmission electron microscope (TEM) analysis showed that DHA significantly reduced the swollen endoplasmic reticulum (ER) in APP/PS1 mice. Western blot analysis indicated that DHA upregulated the level of NeuN, NeuroD, MAP2, and synaptophysin and promoted neurite outgrowth. Meanwhile, DHA greatly corrected the abnormal levels of Brain-derived neurotrophic factor (BDNF) and rescued the neuronal loss in the hippocampal CA1 area. Western blot analysis revealed that DHA notably down-regulated the protein expression of full length caspase-3, cleaved caspase-3 and Bax. In parallel, the expression of the anti-apoptotic protein Bcl-2 increased after oral DHA treatment.

Results:Altogether, these results indicate that DHA protected AD mice from neuron loss via promoting the expression of BDNF and other neuroplasticity-associated proteins and suppressing the inhibition of neuronal apoptosis.

Keywords: Alzheimer`s disease, amyloid-beta, dihydroartemisinin, apoptosis, synaptophysin, BDNF.

[1]
Barnham KJ, Cappai R, Beyreuther K, Masters CL, Hill AF. Delineating common molecular mechanisms in Alzheimer’s and prion diseases. Trends Biochem Sci 2006; 31(8): 465-72.
[http://dx.doi.org/10.1016/j.tibs.2006.06.006 ] [PMID: 16820299]
[2]
Lesné S, Koh MT, Kotilinek L, et al. A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006; 440(7082): 352-7.
[http://dx.doi.org/10.1038/nature04533 ] [PMID: 16541076]
[3]
Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996; 274(5284): 99-102.
[http://dx.doi.org/10.1126/science.274.5284.99 ] [PMID: 8810256]
[4]
Ankarcrona M, Winblad B. Biomarkers for apoptosis in Alzheimer’s disease. Int J Geriatr Psychiatry 2005; 20(2): 101-5.
[http://dx.doi.org/10.1002/gps.1260 ] [PMID: 15660410]
[5]
Tiwari S, Atluri V, Kaushik A, Yndart A, Nair M. Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics. Int J Nanomedicine 2019; 14: 5541-54.
[http://dx.doi.org/10.2147/IJN.S200490 ] [PMID: 31410002]
[6]
Thal DR, Griffin WS, Braak H. Parenchymal and vascular Abeta-deposition and its effects on the degeneration of neurons and cognition in Alzheimer’s disease. J Cell Mol Med 2008; 12(5B): 1848-62.
[http://dx.doi.org/10.1111/j.1582-4934.2008.00411.x ] [PMID: 18624777]
[7]
Hashimoto S, Saido TC. Critical review: involvement of endoplasmic reticulum stress in the aetiology of Alzheimer’s disease. Open Biol 2018; 8(4)180024
[http://dx.doi.org/10.1098/rsob.180024 ] [PMID: 29695619]
[8]
Tanila H. The role of BDNF in Alzheimer’s disease. Neurobiol Dis 2017; 97(Pt B): 114-8.
[9]
Lu B, Chow A. Neurotrophins and hippocampal synaptic transmission and plasticity. J Neurosci Res 1999; 58(1): 76-87.
[http://dx.doi.org/10.1002/(SICI)1097-4547(19991001)58:1<76::AID-JNR8>3.0.CO;2-0 ] [PMID: 10491573]
[10]
Reiss AB, Arain HA, Stecker MM, Siegart NM, Kasselman LJ. Amyloid toxicity in Alzheimer’s disease. Rev Neurosci 2018; 29(6): 613-27.
[http://dx.doi.org/10.1515/revneuro-2017-0063 ] [PMID: 29447116]
[11]
Kim R. Unknotting the roles of Bcl-2 and Bcl-xL in cell death. Biochem Biophys Res Commun 2005; 333(2): 336-43.
[http://dx.doi.org/10.1016/j.bbrc.2005.04.161 ] [PMID: 15922292]
[12]
Friedlander RM. Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 2003; 348(14): 1365-75.
[http://dx.doi.org/10.1056/NEJMra022366 ] [PMID: 12672865]
[13]
Copani A, Melchiorri D, Caricasole A, et al. β-amyloid-induced synthesis of the ganglioside GD3 is a requisite for cell cycle reactivation and apoptosis in neurons. J Neurosci 2002; 22(10): 3963-8.
[http://dx.doi.org/10.1523/JNEUROSCI.22-10-03963.2002 ] [PMID: 12019315]
[14]
Klimova B, Kuca K. Alzheimer’s Disease and Chinese Medicine as a useful alternative intervention tool: a mini-review. Curr Alzheimer Res 2017; 14(6): 680-5.
[http://dx.doi.org/10.2174/1567205014666170117103656 ] [PMID: 28124587]
[15]
Lam NS, Long X, Su XZ, Lu F. Artemisinin and its derivatives in treating helminthic infections beyond schistosomiasis. Pharmacol Res 2018; 133: 77-100.
[http://dx.doi.org/10.1016/j.phrs.2018.04.025 ] [PMID: 29727708]
[16]
Kloprogge F, Workman L, Borrmann S, et al. Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: a pharmacokinetic-pharmacodynamic meta-analysis. PLoS Med 2018; 15(6): e1002579.
[http://dx.doi.org/10.1371/journal.pmed.1002579 ] [PMID: 29894518]
[17]
Lohy Das J, Rulisa S, de Vries PJ, et al. Population pharmacokinetics of artemether, dihydroartemisinin, and lumefantrine in rwandese pregnant women treated for uncomplicated plasmodium falciparum malaria. Antimicrob Agents Chemother 2018; 62(10): e00518-18.
[http://dx.doi.org/10.1128/AAC.00518-18 ] [PMID: 30061282]
[18]
Qiang W, Cai W, Yang Q, et al. Artemisinin b improves learning and memory impairment in AD dementia mice by suppressing neuroinflammation. Neuroscience 2018; 395: 1-12.
[http://dx.doi.org/10.1016/j.neuroscience.2018.10.041 ] [PMID: 30399421]
[19]
Zhao X, Fang J, Li S, et al. Artemisinin attenuated hydrogen peroxide (H2O2)-induced oxidative injury in SH-SY5Y and hippocampal neurons via the activation of AMPK pathway. Int J Mol Sci 2019; 20(11): E2680.
[http://dx.doi.org/10.3390/ijms20112680 ] [PMID: 31151322]
[20]
Zeng Z, Xu J, Zheng W. Artemisinin protects PC12 cells against β-amyloid-induced apoptosis through activation of the ERK1/2 signaling pathway. Redox Biol 2017; 12: 625-33.
[http://dx.doi.org/10.1016/j.redox.2017.04.003 ] [PMID: 28391183]
[21]
Tai X, Cai XB, Zhang Z, Wei R. In vitro and in vivo inhibition of tumor cell viability by combined dihydroartemisinin and doxorubicin treatment, and the underlying mechanism. Oncol Lett 2016; 12(5): 3701-6.
[http://dx.doi.org/10.3892/ol.2016.5187 ] [PMID: 27900057]
[22]
Wu C, Liu J, Pan X, et al. Design, synthesis and evaluation of the antibacterial enhancement activities of amino dihydroartemisinin derivatives. Molecules 2013; 18(6): 6866-82.
[http://dx.doi.org/10.3390/molecules18066866 ] [PMID: 23752470]
[23]
Zhang XG, Li GX, Zhao SS, Xu FL, Wang YH, Wang W. A review of dihydroartemisinin as another gift from traditional Chinese medicine not only for malaria control but also for schistosomiasis control. Parasitol Res 2014; 113(5): 1769-73.
[http://dx.doi.org/10.1007/s00436-014-3822-z ] [PMID: 24609234]
[24]
Zhao Y, Long Z, Ding Y, et al. Dihydroartemisinin ameliorates learning and memory in Alzheimer’s disease through promoting autophagosome-lysosome fusion and autolysosomal degradation for Aβ clearance. Front Aging Neurosci 2020; 12: 47.
[http://dx.doi.org/10.3389/fnagi.2020.00047 ] [PMID: 32210783]
[25]
Peters W, Fleck SL, Robinson BL, Stewart LB, Jefford CW. The chemotherapy of rodent malaria. LX. The importance of formulation in evaluating the blood schizontocidal activity of some endoperoxide antimalarials. Ann Trop Med Parasitol 2002; 96(6): 559-73.
[http://dx.doi.org/10.1179/000349802125001744 ] [PMID: 12396319]
[26]
Long Z, Zeng Q, Wang K, Sharma A, He G. Gender difference in valproic acid-induced neuroprotective effects on APP/PS1 double transgenic mice modeling Alzheimer’s disease. Acta Biochim Biophys Sin (Shanghai) 2016; 48(10): 930-8.
[http://dx.doi.org/10.1093/abbs/gmw085 ] [PMID: 27614317]
[27]
Long ZM, Zhao L, Jiang R, et al. Valproic acid modifies synaptic structure and accelerates neurite outgrowth via the glycogen synthase kinase-3β signaling pathway in an Alzheimer’s disease model. CNS Neurosci Ther 2015; 21(11): 887-97.
[http://dx.doi.org/10.1111/cns.12445 ] [PMID: 26385876]
[28]
Skaper SD, Facci L, Zusso M, Giusti P. Synaptic plasticity, dementia and Alzheimer disease. CNS Neurol Disord Drug Targets 2017; 16(3): 220-33.
[http://dx.doi.org/10.2174/1871527316666170113120853 ] [PMID: 28088900]
[29]
Navipour E, Neamatshahi M, Barabadi Z, Neamatshahi M, Keykhosravi A. Epidemiology and risk factors of alzheimer’s disease in Iran: a systematic review. Iran J Public Health 2019; 48(12): 2133-9.
[PMID: 31993381]
[30]
Obulesu M, Rao DM. Animal models of Alzheimer’s disease: an understanding of pathology and therapeutic avenues. Int J Neurosci 2010; 120(8): 531-7.
[http://dx.doi.org/10.3109/00207451003760080 ] [PMID: 20615056]
[31]
Wright JW, Harding JW. The brain RAS and Alzheimer’s disease. Exp Neurol 2010; 223(2): 326-33.
[http://dx.doi.org/10.1016/j.expneurol.2009.09.012 ] [PMID: 19782074]
[32]
van der Kant R, Goldstein LSB, Ossenkoppele R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat Rev Neurosci 2020; 21(1): 21-35.
[http://dx.doi.org/10.1038/s41583-019-0240-3 ] [PMID: 31780819]
[33]
Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001; 24: 677-736.
[http://dx.doi.org/10.1146/annurev.neuro.24.1.677 ] [PMID: 11520916]
[34]
Chen G, Fan Z, Wang X, et al. Brain-derived neurotrophic factor suppresses tunicamycin-induced upregulation of CHOP in neurons. J Neurosci Res 2007; 85(8): 1674-84.
[http://dx.doi.org/10.1002/jnr.21292 ] [PMID: 17455323]
[35]
Shimoke K, Utsumi T, Kishi S, et al. Prevention of endoplasmic reticulum stress-induced cell death by brain-derived neurotrophic factor in cultured cerebral cortical neurons. Brain Res 2004; 1028(1): 105-11.
[http://dx.doi.org/10.1016/j.brainres.2004.09.005 ] [PMID: 15518647]
[36]
Jeong S. Molecular and cellular basis of neurodegeneration in Alzheimer’s disease. Mol Cells 2017; 40(9): 613-20.
[PMID: 28927263]
[37]
Sánchez-Rodríguez I, Djebari S, Temprano-Carazo S, et al. Hippocampal long-term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G-protein-gated inwardly rectifying potassium channel activity. J Neurochem 2020; 153(3): e14946.
[38]
Lumkwana D, du Toit A, Kinnear C, Loos B. Autophagic flux control in neurodegeneration: progress and precision targeting-where do we stand? Prog Neurobiol 2017; 153: 64-85.
[http://dx.doi.org/10.1016/j.pneurobio.2017.03.006 ] [PMID: 28385648]
[39]
Jang SS, Chung HJ. Emerging link between Alzheimer’s disease and homeostatic synaptic plasticity. Neural Plast 2016; 2016: 7969272.
[http://dx.doi.org/10.1155/2016/7969272 ] [PMID: 27019755]
[40]
Qiu L-L, Pan W, Luo D, et al. Dysregulation of BDNF/TrkB signaling mediated by NMDAR/Ca2+/calpain might contribute to postoperative cognitive dysfunction in aging mice. J Neuroinflammation 2020; 17(1): 23.
[http://dx.doi.org/10.1186/s12974-019-1695-x ] [PMID: 31948437]
[41]
Garzon D, Yu G, Fahnestock M. A new brain-derived neurotrophic factor transcript and decrease in brain-derived neurotrophic factor transcripts 1, 2 and 3 in Alzheimer’s disease parietal cortex. J Neurochem 2002; 82(5): 1058-64.
[http://dx.doi.org/10.1046/j.1471-4159.2002.01030.x ] [PMID: 12358753]
[42]
Fahnestock M, Garzon D, Holsinger RM, Michalski B. Neurotrophic factors and Alzheimer’s disease: are we focusing on the wrong molecule? J Neural Transm Suppl 2002; 62(62): 241-52.
[http://dx.doi.org/10.1007/978-3-7091-6139-5_22 ] [PMID: 12456067]
[43]
Peng S, Wuu J, Mufson EJ, Fahnestock M. Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J Neurochem 2005; 93(6): 1412-21.
[http://dx.doi.org/10.1111/j.1471-4159.2005.03135.x ] [PMID: 15935057]
[44]
Peng S, Garzon DJ, Marchese M, et al. Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer’s disease. J Neurosci 2009; 29(29): 9321-9.
[http://dx.doi.org/10.1523/JNEUROSCI.4736-08.2009 ] [PMID: 19625522]
[45]
Ghavami S, Shojaei S, Yeganeh B, et al. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol 2014; 112: 24-49.
[http://dx.doi.org/10.1016/j.pneurobio.2013.10.004 ] [PMID: 24211851]
[46]
Yang DS, Kumar A, Stavrides P, et al. Neuronal apoptosis and autophagy cross talk in aging PS/APP mice, a model of Alzheimer’s disease. Am J Pathol 2008; 173(3): 665-81.
[http://dx.doi.org/10.2353/ajpath.2008.071176] [PMID: 18688038]

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