Geniposide Protects Primary Cortical Neurons Against Oligomeric Aβ1-42-Induced Neurotoxicity Through a Mitochondrial Pathway

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2016 Apr 6

PMID 27046221

Citations 22

Authors

Chunhui Zhao

Cui Lv

Hang Li

Shijing Du

Xiaoli Liu

Zhi Li

Wenfeng Xin

Wensheng Zhang

Affiliations

Soon will be listed here.

Abstract

Mitochondrial dysfunction plays a key role in the progression of Alzheimer's disease (AD). The accumulation of amyloid-beta peptide (Aβ) in the brains of AD patients is thought to be closely related to neuronal mitochondrial dysfunction and oxidative stress. Therefore, protecting mitochondria from Aβ-induced neurotoxicity is an effective strategy for AD therapeutics. In a previous study, we found that geniposide, a pharmacologically active compound purified from gardenia fruit, has protective effects on oxidative stress and mitochondrial dysfunction in AD transgenic mouse models. However, whether geniposide has a protective effect on Aβ-induced neuronal dysfunction remains unknown. In the present study, we demonstrate that geniposide protects cultured primary cortical neurons from Aβ-mediated mitochondrial dysfunction by recovering ATP generation, mitochondrial membrane potential (MMP), and cytochrome c oxidase (CcO) and caspase 3/9 activity; by reducing ROS production and cytochrome c leakage; as well as by inhibiting apoptosis. These findings suggest that geniposide may attenuate Aβ-induced neuronal injury by inhibiting mitochondrial dysfunction and oxidative stress.

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References

de la Monte S, Wands J . Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease. J Alzheimers Dis. 2006; 9(2):167-81. DOI: 10.3233/jad-2006-9209. View

Broe M, Shepherd C, Milward E, Halliday G . Relationship between DNA fragmentation, morphological changes and neuronal loss in Alzheimer's disease and dementia with Lewy bodies. Acta Neuropathol. 2001; 101(6):616-24. DOI: 10.1007/s004010000337. View

Ferri C, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M . Global prevalence of dementia: a Delphi consensus study. Lancet. 2005; 366(9503):2112-7. PMC: 2850264. DOI: 10.1016/S0140-6736(05)67889-0. View

Gotz J, Eckert A, Matamales M, Ittner L, Liu X . Modes of Aβ toxicity in Alzheimer's disease. Cell Mol Life Sci. 2011; 68(20):3359-75. PMC: 3181413. DOI: 10.1007/s00018-011-0750-2. View

Li Z, Li H, Zhao C, Lv C, Zhong C, Xin W . Protective Effect of Notoginsenoside R1 on an APP/PS1 Mouse Model of Alzheimer's Disease by Up-Regulating Insulin Degrading Enzyme and Inhibiting Aβ Accumulation. CNS Neurol Disord Drug Targets. 2015; 14(3):360-9. DOI: 10.2174/1871527314666150225141521. View

Wautier M, Chappey O, Corda S, STERN D, Schmidt A, Wautier J . Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab. 2001; 280(5):E685-94. DOI: 10.1152/ajpendo.2001.280.5.E685. View

Hardy J, Selkoe D . The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002; 297(5580):353-6. DOI: 10.1126/science.1072994. View

Liu J, Yin F, Zheng X, Jing J, Hu Y . Geniposide, a novel agonist for GLP-1 receptor, prevents PC12 cells from oxidative damage via MAP kinase pathway. Neurochem Int. 2007; 51(6-7):361-9. DOI: 10.1016/j.neuint.2007.04.021. View

Dragicevic N, Mamcarz M, Zhu Y, Buzzeo R, Tan J, Arendash G . Mitochondrial amyloid-beta levels are associated with the extent of mitochondrial dysfunction in different brain regions and the degree of cognitive impairment in Alzheimer's transgenic mice. J Alzheimers Dis. 2010; 20 Suppl 2:S535-50. DOI: 10.3233/JAD-2010-100342. View

10.

Chen Y, Yeh C, Lo H, Su S, Hseu Y, Hsu L . Generation of reactive oxygen species mediates butein-induced apoptosis in neuroblastoma cells. Oncol Rep. 2012; 27(4):1233-7. PMC: 3583478. DOI: 10.3892/or.2012.1632. View

11.

Kirkland R, Franklin J . Bax, reactive oxygen, and cytochrome c release in neuronal apoptosis. Antioxid Redox Signal. 2003; 5(5):589-96. DOI: 10.1089/152308603770310257. View

12.

Silva D, Selfridge J, Lu J, E L, Cardoso S, Swerdlow R . Mitochondrial abnormalities in Alzheimer's disease: possible targets for therapeutic intervention. Adv Pharmacol. 2012; 64:83-126. PMC: 3625400. DOI: 10.1016/B978-0-12-394816-8.00003-9. View

13.

Eckert A, Hauptmann S, Scherping I, Meinhardt J, Rhein V, Drose S . Oligomeric and fibrillar species of beta-amyloid (A beta 42) both impair mitochondrial function in P301L tau transgenic mice. J Mol Med (Berl). 2008; 86(11):1255-67. DOI: 10.1007/s00109-008-0391-6. View

14.

Gao C, Liu Y, Jiang Y, Ding J, Li L . Geniposide ameliorates learning memory deficits, reduces tau phosphorylation and decreases apoptosis via GSK3β pathway in streptozotocin-induced alzheimer rat model. Brain Pathol. 2013; 24(3):261-9. PMC: 8029432. DOI: 10.1111/bpa.12116. View

15.

Yan S, Stern D . Mitochondrial dysfunction and Alzheimer's disease: role of amyloid-beta peptide alcohol dehydrogenase (ABAD). Int J Exp Pathol. 2005; 86(3):161-71. PMC: 2517415. DOI: 10.1111/j.0959-9673.2005.00427.x. View

16.

Swerdlow R . Alzheimer's disease pathologic cascades: who comes first, what drives what. Neurotox Res. 2011; 22(3):182-94. PMC: 3635146. DOI: 10.1007/s12640-011-9272-9. View

17.

Liu J, Zhang Y, Deng X, Yin F . Geniposide decreases the level of Aβ1-42 in the hippocampus of streptozotocin-induced diabetic rats. Acta Biochim Biophys Sin (Shanghai). 2013; 45(9):787-91. DOI: 10.1093/abbs/gmt069. View

18.

Dahlgren K, Manelli A, Stine Jr W, Baker L, Krafft G, LaDu M . Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem. 2002; 277(35):32046-53. DOI: 10.1074/jbc.M201750200. View

19.

Chin D, Hagl S, Hoehn A, Huebbe P, Pallauf K, Grune T . Adenosine triphosphate concentrations are higher in the brain of APOE3- compared to APOE4-targeted replacement mice and can be modulated by curcumin. Genes Nutr. 2014; 9(3):397. PMC: 4026431. DOI: 10.1007/s12263-014-0397-3. View

20.

Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader J . Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimer's disease. FASEB J. 2005; 19(14):2040-1. DOI: 10.1096/fj.05-3735fje. View