Skip to main content

Advertisement

SpringerLink
Log in

Enhanced Autophagy Contributes to Protective Effects of GM1 Ganglioside Against Aβ1-42-Induced Neurotoxicity and Cognitive Deficits

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. The aggregation of Aβ peptides, Aβ1-42 in particular, is thought to be a fundamental pathogenic mechanism leading to the neuronal damage in AD. Recently, monosialoganglioside GM1 is reported to possess pivotal neuroprotection in neurodegenerative diseases. Previous studies have focused on the conformational dynamics and the biochemical interaction of the amyloid-peptide with the GM1 ganglioside, as well as the protective effect of GM1 on cognition. However, the phenomenon of autophagy with regard to neuronal dysfunction in AD is less investigated. In the present study, GM1 treatment were investigated in an AD mouse model and cultured PC12 dells to examine cognition-protective and neuroprotective effects of GM1. Furthermore, GM1 was found to induce autophagy via testing light chain 3 (LC3), Beclin1, neighbor of BRCA1 gene 1 protein and p62 (a substrate of LC3). Chloroquine, an inhibitor of lysosomal, was used to exclude the interference of lysosome, which could fuse with autophagosome and then clear it. In the presence of the inhibitor of autophagy (3-methyladenine; 3-MA), the protective effect of GM1 on PC12 cells in Aβ (1-42) induced toxic conditions was diminished. Interestingly, the expression of histone deacetylase 1 was increased in PC12 cells when treated with GM1, indicating that autophagy might be activated by GM1 through a pathway integrates protein acetylation. This study provides a novel insight into the protective role of GM1 against Aβ (1-42)-induced neurotoxicity via enhancing autophagy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bremer EG, Schlessinger J, Hakomori S (1986) Ganglioside-mediated modulation of cell growth. Specific effects of GM3 on tyrosine phosphorylation of the epidermal growth factor receptor. J Biol Chem 261:2434–2440

    CAS  PubMed  Google Scholar 

  2. Allende ML, Proia RL (2002) Lubricating cell signaling pathways with gangliosides. Curr Opin Struct Biol 12:587–592

    Article  CAS  PubMed  Google Scholar 

  3. Vieira KP, e Silva ARDA, Zollner L, Malaguti C, Vilella CA, Zollner RdL (2008) Ganglioside GM1 effects on the expression of nerve growth factor (NGF), Trk-A receptor, proinflammatory cytokines and on autoimmune diabetes onset in non-obese diabetic (NOD) mice. Cytokine 42:92–104

    Article  CAS  PubMed  Google Scholar 

  4. Amaro M, Sachl R, Aydogan G, Mikhalyov II Vacha R, Hof M (2016) GM1 ganglioside inhibits beta-amyloid oligomerization induced by sphingomyelin. Angew Chem Int Ed Engl 55:9411–9415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Chan CS, Gertler TS, Surmeier DJ (2009) Calcium homeostasis, selective vulnerability and Parkinson’s disease. Trends Neurosci 32:249–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ariga T, McDonald MP, Yu RK (2008) Role of ganglioside metabolism in the pathogenesis of Alzheimer’s disease - a review. J Lipid Res 49:1157–1175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Oikawa N, Yamaguchi H, Ogino K, Taki T, Yuyama K, Yamamoto N, Shin R-W, Furukawa K, Yanagisawa K (2009) Gangliosides determine the amyloid pathology of Alzheimer’s disease. Neuroreport 20:1043–1046

    CAS  PubMed  Google Scholar 

  8. Beyer K (2007) Mechanistic aspects of Parkinson’s disease: alpha-synuclein and the biomembrane. Cell Biochem Biophys 47:285–299

    Article  CAS  PubMed  Google Scholar 

  9. Wu G, Lu Z-H, Kulkarni N, Ledeen RW (2012) Deficiency of ganglioside GM1 correlates with Parkinson’s disease in mice and humans. J Neurosci Res 90:1997–2008

    Article  CAS  PubMed  Google Scholar 

  10. Svennerholm L, Brane G, Karlsson I, Lekman A, Ramstrom I, Wikkelso C (2002) Alzheimer disease - effect of continuous intracerebroventricular treatment with GM1 ganglioside and a systematic activation programme. Dement Geriatr Cogn Disord 14:128–136

    Article  CAS  PubMed  Google Scholar 

  11. Valdomero A, Hansen C, Gerez de Burgos N, Cuadra GR, Orsingher OA (2010) GM1 ganglioside enhances the rewarding properties of cocaine in rats. Eur J Pharmacol 630:79–83

    Article  CAS  PubMed  Google Scholar 

  12. Kim J, Klionsky DJ (2000) Autophagy, cytoplasm-to-vacuole targeting pathway, and pexophagy in yeast and mammalian cells. Annu Rev Biochem 69:303–342

    Article  CAS  PubMed  Google Scholar 

  13. Cuervo AM (2004) Autophagy: in sickness and in health. Trends Cell Biol 14:70–77

    Article  PubMed  Google Scholar 

  14. Kimura S, Noda T, Yoshimori T (2007) Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3:452–460

    Article  CAS  PubMed  Google Scholar 

  15. Klionsky DJ (2007) Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8:931–937

    Article  CAS  PubMed  Google Scholar 

  16. Ling D, Song H-J, Garza D, Neufeld TP, Salvaterra PM (2009) Abeta42-induced neurodegeneration via an age-dependent autophagic-lysosomal injury in Drosophila. PLoS ONE 4:e4201

    Article  PubMed  PubMed Central  Google Scholar 

  17. Yorimitsu T, Nair U, Yang Z, Klionsky DJ (2006) Endoplasmic reticulum stress triggers autophagy. J Biol Chem 281:30299–30304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shintani T, Klionsky DJ (2004) Autophagy in health and disease: a double-edged sword. Science 306:990–995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang CW, Klionsky DJ (2003) The molecular mechanism of autophagy. Mol Med 9:65–76

    PubMed  PubMed Central  Google Scholar 

  20. Hung S-Y, Huang W-P, Liou H-C, Fu W-M (2009) Autophogy protects neuron from Aβ-induced cytotoxicity. Autophagy 5:502–510

    Article  CAS  PubMed  Google Scholar 

  21. Doria A, Gatto M, Punzi L (2013) Autophagy in human health and disease. N Engl J Med 368:1845–1845

    Article  CAS  PubMed  Google Scholar 

  22. Gu MY, Kim J, Yang HO (2016) The neuroprotective effects of justicidin A on amyloid beta25-35-induced neuronal cell death through inhibition of tau hyperphosphorylation and induction of autophagy in SH-SY5Y cells. Neurochem Res 41:1458–1467

    Article  CAS  PubMed  Google Scholar 

  23. Park SY, Lee HR, Lee WS, Shin HK, Kim HY, Hong KW, Kim CD (2016) Cilostazol modulates autophagic degradation of β-amyloid peptide via SIRT1-coupled LKB1/AMPKα signaling in neuronal cells. PLoS One 11:e0160620

    Article  PubMed  PubMed Central  Google Scholar 

  24. Moon M, Choi JG, Nam DW, Hong H-S, Choi Y-J, Oh MS, Mook-Jung I (2011) Ghrelin ameliorates cognitive dysfunction and neurodegeneration in intrahippocampal amyloid-beta(1-42) oligomer-injected mice. J Alzheimers Dis 23:147–159

    CAS  PubMed  Google Scholar 

  25. Akillioglu K, Melik EB, Melik E, Kocahan S (2012) The investigation of neonatal MK-801 administration and physical environmental enrichment on emotional and cognitive functions in adult Balb/c mice. Pharmacol Biochem Behav 102:407–414

    Article  CAS  PubMed  Google Scholar 

  26. Llorente-Berzal A, Manzanedo C, Daza-Losada M, Valero M, Lopez-Gallardo M, Aguilar MA, Rodriguez-Arias M, Minarro J, Viveros M-P (2013) Sex-dependent effects of early maternal deprivation on MDMA-induced conditioned place preference in adolescent rats: possible neurochemical correlates. Toxicology 311:78–86

    Article  CAS  PubMed  Google Scholar 

  27. Harrison EL, Jaehne EJ, Jawahar MC, Corrigan F, Baune BT (2014) Maternal separation modifies behavioural and neuroendocrine responses to stress in CCR7 deficient mice. Behav Brain Res 263:169–175

    Article  CAS  PubMed  Google Scholar 

  28. Cheng X, Luo H, Hou Z, Huang Y, Sun J, Zhuo L (2014) Neuronal nitric oxide synthase, as a downstream signaling molecule of c-jun, regulates the survival of differentiated PC12 cells. Mol Med Rep 10:1881–1886

    CAS  PubMed  Google Scholar 

  29. Cheng X, Fu R, Gao M, Liu S, Li YQ, Song FH, Bruce IC, Zhou LH, Wu W (2013) Intrathecal application of short interfering RNA knocks down c-jun expression and augments spinal motoneuron death after root avulsion in adult rats. Neuroscience 241:268–279

    Article  CAS  PubMed  Google Scholar 

  30. Menzies FM, Huebener J, Renna M, Bonin M, Riess O, Rubinsztein DC (2010) Autophagy induction reduces mutant ataxin-3 levels and toxicity in a mouse model of spinocerebellar ataxia type 3. Brain 133:93–104

    Article  PubMed  Google Scholar 

  31. Zheng M, Liu J, Ruan Z, Tian S, Ma Y, Zhu J, Li G (2013) Intrahippocampal injection of Aβ (1-42) inhibits neurogenesis and down-regulates IFN-γ and NF-κB expression in hippocampus of adult mouse brain. Amyloid 20:13–20

    Article  PubMed  Google Scholar 

  32. Kreutz F, Scherer EB, Ferreira AG, dos Santos Petry F, Pereira CL, Santana F, de Souza Wyse AT, Salbego CG, Trindade VM (2013) Alterations on Na(+), K(+)-ATPase and acetylcholinesterase activities induced by amyloid-β peptide in rat brain and GM1 ganglioside neuroprotective action. Neurochem Res 38:2342–2350

    Article  CAS  PubMed  Google Scholar 

  33. Kang B, Mu S, Yang Q, Guo S, Chen X, Guo H (2017) Ape1 protects against MPP+-induced neurotoxicity through ERK1/2 signaling in PC12 cells. NeuroReport 28:10–16

    Article  CAS  PubMed  Google Scholar 

  34. Yanagisawa K, Odaka A, Suzuki N, Ihara Y (1995) GM1 gangloside-bound amyloid beta-protein (AB) - a possible form of preamyloid in Alzheimers-disease. Nat Med 1:1062–1066

    Article  CAS  PubMed  Google Scholar 

  35. Kakio A, Nishimoto S, Yanagisawa K, Kozutsumi Y, Matsuzaki K (2002) Interactions of amyloid beta-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid. BioChemistry 41:7385–7390

    Article  CAS  PubMed  Google Scholar 

  36. Zhang X, Shi H, Lin S, Ba M, Cui S (2015) MicroRNA-216a enhances the radiosensitivity of pancreatic cancer cells by inhibiting beclin-1-mediated autophagy. Oncol Rep 34:1557–1564

    CAS  PubMed  Google Scholar 

  37. Levine B, Liu R, Dong X, Zhong Q (2015) Beclin orthologs: integrative hubs of cell signaling, membrane trafficking, and physiology. Trends Cell Biol 25:533–544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Li X, He L, Che KH, Funderburk SF, Pan L, Pan N, Zhang M, Yue Z, Zhao Y (2012) Imperfect interface of Beclin1 coiled-coil domain regulates homodimer and heterodimer formation with Atg14L and UVRAG. Nat Commun. doi:10.1038/ncomms1648

    Google Scholar 

  39. Suzuki K, Noda T, Ohsumi Y (2004) Interrelationships among Atg proteins during autophagy in Saccharomyces cerevisiae. Yeast 21:1057–1065

    Article  CAS  PubMed  Google Scholar 

  40. Yue ZY, Jin SK, Yang CW, Levine AJ, Heintz N (2003) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci USA 100:15077–15082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cicchini M, Chakrabarti R, Kongara S, Price S, Nahar R, Lozy F, Zhong H, Vazquez A, Kang Y, Karantza V (2014) Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity. Autophagy 10:2036–2052

    Article  PubMed  PubMed Central  Google Scholar 

  42. Jia K, Levine B (2007) Autophagy is required for dietary restriction-mediated life span extension in C-elegans. Autophagy 3:597–599

    Article  PubMed  Google Scholar 

  43. Thoresen SB, Pedersen NM, Liestol K, Stenmark H (2010) A phosphatidylinositol 3-kinase class III sub-complex containing VPS15, VPS34, Beclin 1, UVRAG and BIF-1 regulates cytokinesis and degradative endocytic traffic. Exp Cell Res 316:3368–3378

    Article  CAS  PubMed  Google Scholar 

  44. Deng L, Lei Y, Liu R, Li J, Yuan K, Li Y, Chen Y, Liu Y, Lu Y, Edwards CK 3rd, Huang C, Wei Y (2013) Pyrvinium targets autophagy addiction to promote cancer cell death. Cell Death Dis 4:e614

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hansen M, Chandra A, Mitic LL, Onken B, Driscoll M, Kenyon C (2008) A role for autophagy in the extension of lifespan by dietary restriction in C-elegans. PLoS Genet. doi:10.1371/journal.pgen.0040024

    Google Scholar 

  46. Mitani T, Minami M, Harada N, Ashida H, Yamaji R (2015) Autophagic degradation of the androgen receptor mediated by increased phosphorylation of p62 suppresses apoptosis in hypoxia. Cell Signalling 27:1994–2001

    Article  CAS  PubMed  Google Scholar 

  47. Kanki T, Furukawa K, Yamashita S-I (2015) Mitophagy in yeast: molecular mechanisms and physiological role. Biochim Biophys Acta 1853:2756–2765

    Article  CAS  PubMed  Google Scholar 

  48. Park JS, Kang DH, Bae SH (2015) p62 prevents carbonyl cyanide m-chlorophenyl hydrazine (CCCP)-induced apoptotic cell death by activating Nrf2. Biochem Biophys Res Commun 464:1139–1144

    Article  CAS  PubMed  Google Scholar 

  49. Liu K-P, Zhou D, Ouyang D-Y, Xu L-H, Wang Y, Wang L-X, Pan H, He X-H (2013) LC3B-II deacetylation by histone deacetylase 6 is involved in serum-starvation-induced autophagic degradation. Biochem Biophys Res Commun 441:970–975

    Article  CAS  PubMed  Google Scholar 

  50. Li L, Tian J, Long MK, Chen Y, Lu J, Zhou C, Wang T (2016) Protection against experimental stroke by ganglioside GM1 Is associated with the inhibition of autophagy. PLoS One 11:e0144219

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by Guangdong Provincial Major Science and Technology for Special Program of China (No. 2012A080202017), the Characteristic key Discipline Construction Fund of Chinese Internal Medicine of Guangzhou University of Chinese Medicine and South China Chinese Medicine Collaborative Innovation Center (No. A1-AFD01514A05), the Doctoral Fund of Education Ministry of China (No. 20134425110003).

Author information

Author notes

    Authors and Affiliations

    1. Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, No. 12 Jichang Road, Guangzhou, 510405, Guangdong, People’s Republic of China

      Ruwei Dai, Shijie Zhang, Wenjun Duan, Renrong Wei, Huifang Chen, Weibin Cai, Lei Yang & Qi Wang

    Authors
    1. Ruwei Dai
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Shijie Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Wenjun Duan
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Renrong Wei
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Huifang Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Weibin Cai
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Lei Yang
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Qi Wang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Lei Yang or Qi Wang.

    Ethics declarations

    Conflict of interest

    Authors declared no conflict of interest regarding the publication of this article.

    Additional information

    Ruwei Dai and Shijie Zhang have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Dai, R., Zhang, S., Duan, W. et al. Enhanced Autophagy Contributes to Protective Effects of GM1 Ganglioside Against Aβ1-42-Induced Neurotoxicity and Cognitive Deficits. Neurochem Res 42, 2417–2426 (2017). https://doi.org/10.1007/s11064-017-2266-0

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11064-017-2266-0

    Keywords

    Search

    Navigation