Cornel iridoid glycoside induces autophagy to protect against tau oligomer neurotoxicity induced by the activation of glycogen synthase kinase-3β

  • Cuicui Yang
  • Xuelian Li
  • Li Zhang
  • Yali Li
  • Lin LiEmail author
  • Lan ZhangEmail author
Original Paper


Tau oligomers are the etiologic molecules of Alzheimer’s disease, and correlate strongly with neuronal loss and exhibit neurotoxicity. Recent evidence indicates that small tau oligomers are the most relevant toxic aggregate species. The aim of the present study was to investigate the mechanisms of cornel iridoid glycoside (CIG) on tau oligomers and cognitive functions. We injected wortmannin and GF-109203X (WM/GFX, 200 μM each) into the lateral ventricles to induce tau oligomer and memory impairment in rats. When orally administered with CIG at 60 and 120 mg/kg/day for 14 days, CIG decreased the escape latency in the Morris water maze test. We also found that CIG restored the expression of presynaptic p-synapsin, synaptophysin, and postsynaptic density-95 (PSD-95) decreased by WM/GFX in rat cortex. CIG reduced the accumulation of tau oligomers in the brain of WM/GFX rats and in cells transfected with wild type glycogen synthase kinase-3β (wtGSK-3β). In addition, CIG up-regulated the levels of ATG7, ATG12, Beclin-1, and LC3II in vivo and in vitro, suggesting the restoration of autophagy function. These results suggest that CIG could ameliorate memory deficits and regulate memory-associated synaptic proteins through the clearance of tau oligomers accumulation. Moreover, CIG clears tau oligomers by restoring autophagy function.


Cornel iridoid glycoside Autophagy Tau oligomer Glycogen synthase kinase-3β 



This research was supported by the National Natural Science Foundation of China (Nos. 81703729, 81473373), National Science and Technology Major Project of China (No. 2015ZX09101-016), Beijing New Medical Discipline Grant (XK100270569), and Beijing High-level Health and Technical Personal Plan (Nos. 2011-1-7, 2014-2-014).

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest associated with this manuscript.


  1. 1.
    Wang Y, Martinez-Vicente M, Kruger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E (2009) Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet 18:4153–4170CrossRefGoogle Scholar
  2. 2.
    Ambadipudi S, Biernat J, Riedel D, Mandelkow E, Zweckstetter M (2017) Liquid–liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau. Nat Commun 8:275CrossRefGoogle Scholar
  3. 3.
    Michalski D, Preissler H, Hofmann S, Kacza J, Hartig W (2016) Decline of microtubule-associated protein tau after experimental stroke in differently aged wild-type and 3xTg mice with Alzheimer-like alterations. Neuroscience 330:1–11CrossRefGoogle Scholar
  4. 4.
    Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC (2004) Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62:925–931CrossRefGoogle Scholar
  5. 5.
    Cowan CM, Quraishe S, Mudher A (2012) What is the pathological significance of tau oligomers? Biochem Soc Trans 40:693–697CrossRefGoogle Scholar
  6. 6.
    Lasagna-Reeves CA, Castillo-Carranza DL, Jackson GR, Kayed R (2011) Tau oligomers as potential targets for immunotherapy for Alzheimer's disease and tauopathies. Curr Alzheimer Res 8:659–665CrossRefGoogle Scholar
  7. 7.
    Tiernan CT, Mufson EJ, Kanaan NM, Counts SE (2018) Tau oligomer pathology in nucleus basalis neurons during the progression of Alzheimer disease. J Neuropathol Exp Neurol 77:246–259CrossRefGoogle Scholar
  8. 8.
    Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Sarmiento J, Troncoso J, Jackson GR, Kayed R (2012) Identification of oligomers at early stages of tau aggregation in Alzheimer's disease. FASEB J 26:1946–1959CrossRefGoogle Scholar
  9. 9.
    Castillo-Carranza DL, Gerson JE, Sengupta U, Guerrero-Munoz MJ, Lasagna-Reeves CA, Kayed R (2014) Specific targeting of tau oligomers in Htau mice prevents cognitive impairment and tau toxicity following injection with brain-derived tau oligomeric seeds. J Alzheimers Dis 40(Suppl 1):S97–S111CrossRefGoogle Scholar
  10. 10.
    Sengupta U, Guerrero-Munoz MJ, Castillo-Carranza DL, Lasagna-Reeves CA, Gerson JE, Paulucci-Holthauzen AA, Krishnamurthy S, Farhed M, Jackson GR, Kayed R (2015) Pathological interface between oligomeric alpha-synuclein and tau in synucleinopathies. Biol Psychiatry 78:672–683CrossRefGoogle Scholar
  11. 11.
    Sahara N, Ren Y, Ward S, Binder LI, Suhara T, Higuchi M (2014) Tau oligomers as potential targets for early diagnosis of tauopathy. J Alzheimers Dis 40(Suppl 1):S91–S96CrossRefGoogle Scholar
  12. 12.
    Cardenas-Aguayo MC, Gomez-Virgilio L, DeRosa S, Meraz-Rios MA (2014) The role of tau oligomers in the onset of Alzheimer's disease neuropathology. ACS Chem Neurosci 5:1178–1191CrossRefGoogle Scholar
  13. 13.
    Di Domenico F, Tramutola A, Foppoli C, Head E, Perluigi M, Butterfield DA (2018) mTOR in down syndrome: role in Ass and tau neuropathology and transition to Alzheimer disease-like dementia. Free Radic Biol Med 114:94–101CrossRefGoogle Scholar
  14. 14.
    Wischik CM, Harrington CR, Storey JM (2014) Tau-aggregation inhibitor therapy for Alzheimer's disease. Biochem Pharmacol 88:529–539CrossRefGoogle Scholar
  15. 15.
    Kruger U, Wang Y, Kumar S, Mandelkow EM (2012) Autophagic degradation of tau in primary neurons and its enhancement by trehalose. Neurobiol Aging 33:2291–2305CrossRefGoogle Scholar
  16. 16.
    Umeda T, Ono K, Sakai A, Yamashita M, Mizuguchi M, Klein WL, Yamada M, Mori H, Tomiyama T (2016) Rifampicin is a candidate preventive medicine against amyloid-beta and tau oligomers. Brain 139:1568–1586CrossRefGoogle Scholar
  17. 17.
    Jiang ZQ, Li Y, Jiang LH, Gu H, Wang MY (2013) Hepatoprotective effects of extracts from processed corni fructus against d-galactose-induced liver injury in mice. Zhong Yao Cai 36:85–89Google Scholar
  18. 18.
    Zhang Y, Qiao ZL, Guo L (2012) Clinical research of senile vascular dementia treated with Bushen Yizhi Decoction. World J Integr Tradit West Med 7:594–598Google Scholar
  19. 19.
    Han DJ, Yang XY, Shi J, Tian JZ (2014) Analysis on therapies and medications in randomized controlled trials of TCM for dementia. J Tradit Chin Med 55:1051–1054Google Scholar
  20. 20.
    Ma D, Zhu Y, Li Y, Yang C, Zhang L, Li Y, Li L, Zhang L (2016) Beneficial effects of cornel iridoid glycoside on behavioral impairment and senescence status in SAMP8 mice at different ages. Behav Brain Res 312:20–29CrossRefGoogle Scholar
  21. 21.
    Yang C, Li X, Gao W, Wang Q, Zhang L, Li Y, Li L, Zhang L (2018) Cornel iridoid glycoside inhibits tau hyperphosphorylation via regulating cross-talk between GSK-3beta and PP2A signaling. Front Pharmacol 9:682CrossRefGoogle Scholar
  22. 22.
    Balaraman Y, Limaye AR, Levey AI, Srinivasan S (2006) Glycogen synthase kinase 3beta and Alzheimer's disease: pathophysiological and therapeutic significance. Cell Mol Life Sci 63:1226–1235CrossRefGoogle Scholar
  23. 23.
    Forlenza OV, Torres CA, Talib LL, de Paula VJ, Joaquim HP, Diniz BS, Gattaz WF (2011) Increased platelet GSK3B activity in patients with mild cognitive impairment and Alzheimer's disease. J Psychiatr Res 45:220–224CrossRefGoogle Scholar
  24. 24.
    Avila J, Insausti R, Del RJ (2010) Memory and neurogenesis in aging and Alzheimer's disease. Aging Dis 1:30–36Google Scholar
  25. 25.
    Yao RQ, Zhang L, Wang W, Li L (2009) Cornel iridoid glycoside promotes neurogenesis and angiogenesis and improves neurological function after focal cerebral ischemia in rats. Brain Res Bull 79:69–76CrossRefGoogle Scholar
  26. 26.
    Zhao LH, Ding YX, Zhang L, Li L (2010) Cornel iridoid glycoside improves memory ability and promotes neuronal survival in fimbria-fornix transected rats. Eur J Pharmacol 647:68–74CrossRefGoogle Scholar
  27. 27.
    Yang CC, Kuai XX, Li YL, Zhang L, Yu JC, Li L, Zhang L (2013) Cornel iridoid glycoside attenuates tau hyperphosphorylation by inhibition of PP2A demethylation. Evid Based Complement Altern Med 2013:108486Google Scholar
  28. 28.
    Mizushima N (2007) Autophagy: process and function. Genes Dev 21:2861–2873CrossRefGoogle Scholar
  29. 29.
    Juhasz G, Erdi B, Sass M, Neufeld TP (2007) Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev 21:3061–3066CrossRefGoogle Scholar
  30. 30.
    Martinez A, Perez DI (2008) GSK-3 inhibitors: a ray of hope for the treatment of Alzheimer's disease? J Alzheimers Dis 15:181–191CrossRefGoogle Scholar
  31. 31.
    Pavel M, Imarisio S, Menzies FM, Jimenez-Sanchez M, Siddiqi FH, Wu X, Renna M, O'Kane CJ, Crowther DC, Rubinsztein DC (2016) CCT complex restricts neuropathogenic protein aggregation via autophagy. Nat Commun 7:13821CrossRefGoogle Scholar
  32. 32.
    Pan H, Wang Z, Jiang L, Sui X, You L, Shou J, Jing Z, Xie J, Ge W, Cai X, Huang W, Han W (2014) Autophagy inhibition sensitizes hepatocellular carcinoma to the multikinase inhibitor linifanib. Sci Rep 4:6683CrossRefGoogle Scholar
  33. 33.
    Sydow A, Van der Jeugd A, Zheng F, Ahmed T, Balschun D, Petrova O, Drexler D, Zhou L, Rune G, Mandelkow E, D'Hooge R, Alzheimer C, Mandelkow EM (2011) Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. J Neurosci 31:2511–2525CrossRefGoogle Scholar
  34. 34.
    Sengupta U, Portelius E, Hansson O, Farmer K, Castillo-Carranza D, Woltjer R, Zetterberg H, Galasko D, Blennow K, Kayed R (2017) Tau oligomers in cerebrospinal fluid in Alzheimer's disease. Ann Clin Transl Neurol 4:226–235CrossRefGoogle Scholar
  35. 35.
    Tepper K, Biernat J, Kumar S, Wegmann S, Timm T, Hubschmann S, Redecke L, Mandelkow EM, Muller DJ, Mandelkow E (2014) Oligomer formation of tau protein hyperphosphorylated in cells. J Biol Chem 289:34389–34407CrossRefGoogle Scholar
  36. 36.
    Llorens-Martin M, Fuster-Matanzo A, Teixeira CM, Jurado-Arjona J, Ulloa F, Defelipe J, Rabano A, Hernandez F, Soriano E, Avila J (2013) GSK-3beta overexpression causes reversible alterations on postsynaptic densities and dendritic morphology of hippocampal granule neurons in vivo. Mol Psychiatry 18:451–460CrossRefGoogle Scholar
  37. 37.
    Liu SJ, Zhang AH, Li HL, Wang Q, Deng HM, Netzer WJ, Xu H, Wang JZ (2003) 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 87:1333–1344CrossRefGoogle Scholar
  38. 38.
    Usenovic M, Niroomand S, Drolet RE, Yao L, Gaspar RC, Hatcher NG, Schachter J, Renger JJ, Parmentier-Batteur S (2015) Internalized tau oligomers cause neurodegeneration by inducing accumulation of pathogenic tau in human neurons derived from induced pluripotent stem cells. J Neurosci 35:14234–14250CrossRefGoogle Scholar
  39. 39.
    Liu M, Ni J, Kosik KS, Yeh LA (2004) Development of a fluorescent high throughput assay for tau aggregation. Assay Drug Dev Technol 2:609–619CrossRefGoogle Scholar
  40. 40.
    Coleman PD, Yao PJ (2003) Synaptic slaughter in Alzheimer's disease. Neurobiol Aging 24:1023–1027CrossRefGoogle Scholar
  41. 41.
    Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Clos AL, Jackson GR, Kayed R (2011) Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice. Mol Neurodegener 6:39CrossRefGoogle Scholar
  42. 42.
    Fornasiero EF, Raimondi A, Guarnieri FC, Orlando M, Fesce R, Benfenati F, Valtorta F (2012) Synapsins contribute to the dynamic spatial organization of synaptic vesicles in an activity-dependent manner. J Neurosci 32:12214–12227CrossRefGoogle Scholar
  43. 43.
    Nelson CD, Kim MJ, Hsin H, Chen Y, Sheng M (2013) Phosphorylation of threonine-19 of PSD-95 by GSK-3beta is required for PSD-95 mobilization and long-term depression. J Neurosci 33:12122–12135CrossRefGoogle Scholar
  44. 44.
    Garringer HJ, Murrell J, Sammeta N, Gnezda A, Ghetti B, Vidal R (2013) Increased tau phosphorylation and tau truncation, and decreased synaptophysin levels in mutant BRI2/tau transgenic mice. PLoS ONE 8:e56426CrossRefGoogle Scholar
  45. 45.
    Ulakcsai Z, Bagamery F, Szoko E, Tabi T (2018) The role of autophagy induction in the mechanism of cytoprotective effect of resveratrol. Eur J Pharm Sci 123:135–142CrossRefGoogle Scholar
  46. 46.
    Park KJ, Lee SH, Lee CH, Jang JY, Chung J, Kwon MH, Kim YS (2009) Upregulation of Beclin-1 expression and phosphorylation of Bcl-2 and p53 are involved in the JNK-mediated autophagic cell death. Biochem Biophys Res Commun 382:726–729CrossRefGoogle Scholar
  47. 47.
    Burgoyne JR (2018) Oxidative stress impairs autophagy through oxidation of ATG3 and ATG7. Autophagy 14:1092–1093Google Scholar
  48. 48.
    Pla A, Pascual M, Guerri C (2016) Autophagy constitutes a protective mechanism against ethanol toxicity in mouse astrocytes and neurons. PLoS ONE 11:e153097CrossRefGoogle Scholar
  49. 49.
    Xu L, Shen J, Yu L, Sun J, McQuillan PM, Hu Z, Yan M (2018) Role of autophagy in sevoflurane-induced neurotoxicity in neonatal rat hippocampal cells. Brain Res Bull 140:291–298CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy 2019

Authors and Affiliations

  1. 1.Department of PharmacyXuanwu Hospital of Capital Medical UniversityBeijingChina
  2. 2.Beijing Institute for Brain DisordersBeijingChina
  3. 3.Beijing Engineering Research Center for Nerve System DrugsBeijingChina
  4. 4.Key Laboratory for Neurodegenerative Diseases of Ministry of EducationBeijingChina
  5. 5.Key Laboratory for Basic Pharmacology of Ministry of EducationZunyi Medical CollegeZunyiChina

Personalised recommendations