Cellular and Molecular Neurobiology

, Volume 39, Issue 1, pp 123–135 | Cite as

APC-Cdh1 Regulates Neuronal Apoptosis Through Modulating Glycolysis and Pentose-Phosphate Pathway After Oxygen-Glucose Deprivation and Reperfusion

  • Zuofan Li
  • Bo Zhang
  • Wenlong Yao
  • Chuanhan Zhang
  • Li Wan
  • Yue ZhangEmail author
Original Research


Anaphase-promoting complex (APC) with its coactivator Cdh1 is required to maintain the postmitotic state of neurons via degradation of Cyclin B1, which aims to prevent aberrant cell cycle entry that causes neuronal apoptosis. Interestingly, evidence is accumulating that apart from the cell cycle, APC-Cdh1 also involves in neuronal metabolism via modulating the glycolysis promoting enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). Here, we showed that under oxygen-glucose deprivation and reperfusion (OGD/R), APC-Cdh1 was decreased in primary cortical neurons. Likewise, the neurons exhibited enhanced glycolysis when oxygen supply was reestablished during reperfusion, which was termed as the “neuronal Warburg effect.” In particular, the reperfused neurons showed elevated PFKFB3 expression in addition to a reduction in glucose 6-phosphate dehydrogenase (G6PD). Such changes directed neuronal glucose metabolism from pentose-phosphate pathway (PPP) to aerobic glycolysis compared to the normal neurons, resulting in increased ROS production and apoptosis during reperfusion. Pretreatment of neurons with Cdh1 expressing lentivirus before OGD could reverse this metabolic shift and attenuated ROS-induced apoptosis. However, the metabolism regulation and neuroprotection by Cdh1 under OGD/R condition could be blocked when co-transfecting neurons with Ken box-mut-PFKFB3 (which is APC-Cdh1 insensitive). Based on these data, we suggest that the Warburg effect may contribute to apoptotic mechanisms in neurons under OGD/R insult, and targeting Cdh1 may be a potential therapeutic strategy as both glucose metabolic regulator and apoptosis suppressor of neurons in brain injuries.


Aerobic glycolysis Cdh1 Neuron Oxygen-glucose deprivation Pentose-phosphate pathway 



This work was supported by the National Natural Science Foundation of China (Grant No. 81600965).

Author Contributions

YZ and LW designed the study; ZL and BZ performed the experiments; ZL and WY collected the data and performed the analysis; ZL and CZ wrote the initial draft; YZ contributed towards manuscript improvement and revision.

Compliance with Ethical Standards

Conflict of interest

The author(s) declared they have no financial relationship with the organization that sponsored the research and have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplementary material

10571_2018_638_MOESM1_ESM.tif (12 mb)
Supplementary material 1 (TIF 12241 KB)
10571_2018_638_MOESM2_ESM.tif (4.8 mb)
Supplementary material 2 (TIF 4896 KB)
10571_2018_638_MOESM3_ESM.tif (5.6 mb)
Supplementary material 3 (TIF 5760 KB)
10571_2018_638_MOESM4_ESM.docx (94 kb)
Supplementary material 4 (DOCX 94 KB)


  1. Bashir T, Dorrello N, Amador V, Guardavaccaro D, Pagano M (2004) Control of the SCF (Skp2-Cks1) ubiquitin ligase by the APC/C (Cdh1) ubiquitin ligase. Nature 428:190–193CrossRefGoogle Scholar
  2. Bas-Orth C, Tan YW, Lau D, Bading H (2017) Synaptic activity drives genomic program that promots a neuronal Warburg effect. J Biol Chem 292(13):5183–5194CrossRefGoogle Scholar
  3. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartron R, Gottlieb E, Vousden K. H (2006) TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126:107–120CrossRefGoogle Scholar
  4. Bolaños JP, Almeida A (2010) The Pentose-Phosphate Pathway in Neuronal Survival Against Nitrosative Stress. IUBMB Life 62:14–18Google Scholar
  5. Bolaños JP, Delgado-Esteban M, Herrero-Mendez A, Fernandez- Fernandez S, Almeida A (2008) Regulation of glycolysis and pentose–phosphate pathway by nitric oxide: Impact on neuronal survival. Trends Biochem Sci 35:145–149CrossRefGoogle Scholar
  6. Bolaños JP, Almeida A, Moncada S (2010) Glycolysis: a bioenergetic or a survival pathway? Trends Biochem Sci 35:145–149CrossRefGoogle Scholar
  7. Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51CrossRefGoogle Scholar
  8. Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 21:2–14CrossRefGoogle Scholar
  9. Cheung EC, Ludwig RL, Vousden KH (2012) Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and lowers ROS and cell death. Proc Natl Acad Sci USA 109:20491–20496CrossRefGoogle Scholar
  10. Delgado-Esteban M, Garcia-Higuera I, Maestre C, Moreno S, Almeida A (2013) APC/C-Cdh1 coordinates neurogenesis and cortical size during development. Nat Commun 4:2879CrossRefGoogle Scholar
  11. Dienel GA, Cruz NF (2016) Aerobic glycolysis during brain activation: adrenergic regulation and influence of norepinephrine on astrocytic metabolism. J Neurochem 138:14–52CrossRefGoogle Scholar
  12. Eguren M, Manchado E, Malumbres M (2011) Non-mitotic functions of the anaphase-promoting complex. Semin Cell Dev Biol 22:572–578CrossRefGoogle Scholar
  13. Fu AK, Hung KW, Fu WY, Shen C, Chen Y, Xia J, Lai KO, Lp NY (2011) APC (Cdh1) mediates EphA4-dependent downregulation of AMPA receptors in homeostatic plasticity. Nat Neurosci 14:181–189CrossRefGoogle Scholar
  14. García-Higuera I, Manchado E, Dubus P, Cañamero M, Méndez J, Moreno S, Malumbres M (2008) Genomic stability and tumour suppression by the APC/C cofactor Cdh1. Nat cell boil 10:802–811CrossRefGoogle Scholar
  15. Garcia-Nogales P, Almeida A, Bolaños JP (2003) Peroxynitrite protects neurons against nitric oxide-mediated apoptosis. A key role for glucose-6-phosphate dehydrogenase activity in neuroprotection. J Biol Chem 278:864–874CrossRefGoogle Scholar
  16. Gieffers C, Peters BH, Kramer ER, Dotti CG, Peters JM (1999) Expression of the CDH1-associated form of the anaphase-promoting complex in postmitotic neurons. Proc Natl Acad Sci USA 96:11317–11322CrossRefGoogle Scholar
  17. Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolaños JP (2009) The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol 11:747–752CrossRefGoogle Scholar
  18. Hu R, Li L, Li D, Tan W, Wan L, Zhu C, Zhang Y, Zhang C, Yao W (2016) Downregulation of Cdh1 signaling in spinal dorsal horn contributes to the maintenance of mechanical allodynia after nerve injury in rats. Mol Pain 12:1–16Google Scholar
  19. Huang XJ, Zhang WP, Li CT, Shi WZ, Fang SH, Lu YB, Chen Z, Wei EQ (2008) Activation of CysLT receptors induces astrocyte proliferation and death after oxygen–glucose deprivation. Glia 56:27–37CrossRefGoogle Scholar
  20. Jaquenoud M, van Drogen F, Peter M (2002) Cell cycle-dependent nuclear export of Cdh1p may contribute to the inactivation of APC/C(Cdh1). EMBO J 21:6515–6526CrossRefGoogle Scholar
  21. Kannan M, Lee SJ, Schwedhelm-Domeyer N, Stegmüller J (2012) The E3 ligase Cdh1-anaphase promoting complex operates upstream of the E3 ligase Smurf1 in the control of axon growth. Development 139:3600–3612CrossRefGoogle Scholar
  22. Kim J, Devalaraja-Narashimha K, Padanilam BJ (2015) TIGAR regulates glycolysis in ischemic kidney proximal tubules. Am J Physiol Renal Physiol 308:F298–F308CrossRefGoogle Scholar
  23. Larrabee MG (1990) Evaluation of the pentose phosphate pathway from 14CO2 data. Fallibility of a classic equation when applied to non-homogeneous tissues. Biochem J 272:127–132CrossRefGoogle Scholar
  24. Liu PK, Grossman RG, Hsu CY, Robertson CS (2001) Ischemic injury and faulty gene transcripts in the brain. Trends Neurosci 24:581–588CrossRefGoogle Scholar
  25. Lv Y, Zhang B, Zhai C, Zhang Y, Yao W, Zhang C (2015) PFKFB3-mediated glycolysis is involved in reactive astrocyte proliferation after oxygen-glucose deprivation/ reperfusion and is regulated by Cdh1. Neurochem Int 91:26–33CrossRefGoogle Scholar
  26. Madan E, Gogna R, Kuppusamy P, Bhatt M, Pati U, Mahdi AA (2012) TIGAR induces p53-mediated cell-cycle arrest by regulation of RB-E2F1 complex. Br J Cancer 107:516–526CrossRefGoogle Scholar
  27. Magistretti PJ (2016) Imaging brain aerobic glycolysis as a marker of synaptic plasticity. Proc Natl Acad Sci USA 113: 7015–7016CrossRefGoogle Scholar
  28. McLaughlin BA, Nelson D, Silver IA, Erecinska M, Chesselet MF (1998) Methylmalonate toxicity in primary neuronal cultures. Neuroscience 86:279–290CrossRefGoogle Scholar
  29. Newington JT, Pitts A, Chien A, Arseneault R, Schubert D, Cumming RC (2011) Amyloid beta resistance in nerve cell lines is mediated by the Warburg effect. PLoS ONE 6(4):e19191CrossRefGoogle Scholar
  30. Peters JM (2006) The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol 7:644–656CrossRefGoogle Scholar
  31. Qiu J, Zhang C, Lv Y, Zhang Y, Zhu C, Wang X, Yao W (2013) Cdh1 inhibits reactive astrocyte proliferation after oxygen-glucose deprivation and reperfusion. Neurochem Int 63:87–92CrossRefGoogle Scholar
  32. Raichle ME, Mintun MA (2006) Brain work and brain imaging. Annu Rev Neurosci 29:449–476CrossRefGoogle Scholar
  33. Rodriguez-Rodriguez P, Fernandez E, Almeida A, Bolaños JP (2012) Excitotoxic stimulus stabilizes PFKFB3 causing pentose-phosphate pathway to glycolysis switch and neurodegeneration. Cell Death Differ 19:1582–1589CrossRefGoogle Scholar
  34. Schapira AH (2009) Neurobiology and treatment of Parkinson’s disease. Trends Pharmacol Sci 30:41–47CrossRefGoogle Scholar
  35. Stegmüller J, Konishi Y, Huynh M, Yuan Z, Dibacco S, Bonni A (2006) Cell-intrinsic regulation of axonal morphogenesis by the Cdh1-APC target SnoN. Neuron 50:389–400CrossRefGoogle Scholar
  36. Støttrup NB, Løfgren B, Birkler RD, Nielsen JM, Wang L, Caldarone CA, Kristiansen SB, Contractor H, Johannsen M, Bøtker HE, Nielsen TT (2010) Inhibition of the malate–aspartate shuttle by pre-ischaemic aminooxyacetate loading of the heart induces cardioprotection. Cardiovasc Res 88:257–266CrossRefGoogle Scholar
  37. Sun JH, Ren XF, Qi W, Yuan D, Simpkin JW (2016) Geissoschizine Methyl ether protects oxidative stress-mediated cytotoxicity in neurons through the ‘Neuronal Warburg Effect’. J Ethnopharmacol 187:249–258CrossRefGoogle Scholar
  38. Tan W, Yao W, Hu R, Lv Y, Wan L, Zhang C, Zhu C (2015) Alleviating neuropathic pain mechanical allodynia by increasing Cdh1 in the anterior cingulate cortex. Mol Pain 11:56CrossRefGoogle Scholar
  39. TeSlaa T, Teitell MA (2014) Techniques to monitor glycolysis. Methods Enzymol 542:91–114CrossRefGoogle Scholar
  40. Vander Heiden MG, Christofk HR, Schuman E, Subtelny AO, Sharfi H, Harlow EE, Xian J, Cantlay LC (2010) Identification of small molecule inhibitors of pyruvate kinase M2. Pharm Biol 79:1118–1124Google Scholar
  41. Ventura F, Rosa JL, Ambrosio S, Gil J, Bartrons R (1991) 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase in rat brain. Biochem J 276:455–460CrossRefGoogle Scholar
  42. Vincent I, Jicha G, Rosado M, Dickson D (1997) Aberrant expression of mitotic cdc2/cyclin B1 kinase in degenerating neurons of Alzheimer’s disease brain. J Neurosci 17:3588–3598CrossRefGoogle Scholar
  43. Yao W, Qian W, Zhu C, Gui L, Qiu J, Zhang C (2010) Cdh1-APC is involved in the differentiation of neural stem cells into neurons. Neuroreport 21:39–44CrossRefGoogle Scholar
  44. Zhang Y, Yao W, Qiu J, Qian W, Zhu C, Zhang C (2011) The involvement of down-regulation of Cdh1–APC in hippocampal neuronal apoptosis after global cerebral ischemia in rat. Neurosci Lett 505:71–75CrossRefGoogle Scholar
  45. Zhang B, Wei K, Li X, Hu R, Qiu J, Zhang Y, Yao W, Zhang C, Zhu C (2018) Upregulation of Cdh1 signaling in the hippocampus attenuates brain damage after transient global cerebral ischemia in rats. Neurochem Int 112:166–178CrossRefGoogle Scholar
  46. Zhou Y, Ching YP, Chun AC, Jin DY (2003) Nuclear localization of the cell cycle regulator CDH1 and its regulation by phosphoryla- tion. J Biol Chem 278:12530–12536CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Anesthesiology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

Personalised recommendations