Neurochemical Research

, Volume 38, Issue 11, pp 2237–2246 | Cite as

Neuregulin1beta1 Antagonizes Apoptosis Via ErbB4-Dependent Activation of PI3-Kinase/Akt in APP/PS1 Transgenic Mice

Original Paper


Alzheimer’s disease (AD) is characterized by the deposition of beta-amyloid protein (Aβ) and extensive neuronal cell death. Apoptosis plays a crucial role in loss of neurons in AD. Neuregulin1 (NRG1) has been found to protect neurons from oxygen glucose deprivation induced apoptosis and hypoxia ischemia induced apoptosis. However, the relationship between NRG1 and apoptosis related protein expression in AD and its mechanism remain uncertain. The present study explores the effects of NRG1 on Aβ-induced apoptosis in AD. In this study, extracellular domain of NRG1beta1 (NRG1β1-ECD) promoted the expression of p-ErbB4 receptor, p-Akt and increased the level of Bcl-2 both in APP/PS1 transgenic mice and in vitro. In primary culture of neurons, the level of Bcl-2 protein decreased significantly after Aβ treatment. These changes were inhibited by pretreatment of neurons with NRG1β1-ECD. A specific inhibitor of PI3-kinase/Akt pathway, wortmannin, significantly abrogated the effects of NRG1β1-ECD on p-Akt and Bcl-2 levels. Furthermore, the expression of PI3-kinase/Akt by NRG1β1-ECD was ErbB4-dependent. Our data demonstrated that NRG1β1-ECD might serve as an obvious neuroprotection in AD, and the possible protective mechanism occurs most likely via ErbB4-dependent activation of PI3-kinase/Akt pathway.


Neuregulin1 Apoptosis PI3-kinase/Akt pathway ErbB4 Alzheimer’s disease 



This work was supported by the Science and Technology Project of Department of Education of Henan Province (No. 13A310862), the Key Research Areas of Xinxiang Medical University (No. ZD2011-28, ZD2011-14), the Doctoral Scientific Research Activation Foundation of Xinxiang Medical University, Natural Science Foundation of Jiangxi Province, China (No. 20114BAB205063), and National Natural Science Foundation of China (No. 81260211). We would also like to express thanks to Professors Guomin Zhou and Zulin Chen for introducing the animal model.


  1. 1.
    Selkoe DJ (2001) Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid beta-protein. J Alzheimer’s Dis (JAD) 3(1):75–80Google Scholar
  2. 2.
    Su JH, Anderson AJ, Cummings BJ, Cotman CW (1994) Immunohistochemical evidence for apoptosis in Alzheimer’s disease. NeuroReport 5(18):2529–2533PubMedCrossRefGoogle Scholar
  3. 3.
    Yagami T, Ueda K, Asakura K, Sakaeda T, Nakazato H, Kuroda T, Hata S, Sakaguchi G, Itoh N, Nakano T, Kambayashi Y, Tsuzuki H (2002) Gas6 rescues cortical neurons from amyloid beta protein-induced apoptosis. Neuropharmacology 43(8):1289–1296PubMedCrossRefGoogle Scholar
  4. 4.
    Wang DM, Li SQ, Zhu XY, Wang Y, Wu WL, Zhang XJ (2013) Protective effects of hesperidin against amyloid-beta (Abeta) induced neurotoxicity through the voltage dependent anion channel 1 (VDAC1)-mediated mitochondrial apoptotic pathway in PC12 cells. Neurochem Res 38(5):1034–1044PubMedCrossRefGoogle Scholar
  5. 5.
    Abe-Dohmae S, Harada N, Yamada K, Tanaka R (1993) Bcl-2 gene is highly expressed during neurogenesis in the central nervous system. Biochem Biophys Res Commun 191(3):915–921PubMedCrossRefGoogle Scholar
  6. 6.
    Ferreiro E, Eufrasio A, Pereira C, Oliveira CR, Rego AC (2007) Bcl-2 overexpression protects against amyloid-beta and prion toxicity in GT1-7 neural cells. J Alzheimer’s Dis (JAD) 12(3):223–228Google Scholar
  7. 7.
    Clementi ME, Pezzotti M, Orsini F, Sampaolese B, Mezzogori D, Grassi C, Giardina B, Misiti F (2006) Alzheimer’s amyloid beta-peptide (1-42) induces cell death in human neuroblastoma via bax/bcl-2 ratio increase: an intriguing role for methionine 35. Biochem Biophys Res Commun 342(1):206–213PubMedCrossRefGoogle Scholar
  8. 8.
    Buonanno A, Fischbach GD (2001) Neuregulin and ErbB receptor signaling pathways in the nervous system. Curr Opin Neurobiol 11(3):287–296PubMedCrossRefGoogle Scholar
  9. 9.
    Lopez-Bendito G, Cautinat A, Sanchez JA, Bielle F, Flames N, Garratt AN, Talmage DA, Role LW, Charnay P, Marin O, Garel S (2006) Tangential neuronal migration controls axon guidance: a role for neuregulin-1 in thalamocortical axon navigation. Cell 125(1):127–142PubMedCrossRefGoogle Scholar
  10. 10.
    Mei L, Xiong WC (2008) Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci 9(6):437–452PubMedCrossRefGoogle Scholar
  11. 11.
    Li BS, Ma W, Jaffe H, Zheng Y, Takahashi S, Zhang L, Kulkarni AB, Pant HC (2003) Cyclin-dependent kinase-5 is involved in neuregulin-dependent activation of phosphatidylinositol 3-kinase and Akt activity mediating neuronal survival. J Biol Chem 278(37):35702–35709PubMedCrossRefGoogle Scholar
  12. 12.
    Zhang L, Fletcher-Turner A, Marchionni MA, Apparsundaram S, Lundgren KH, Yurek DM, Seroogy KB (2004) Neurotrophic and neuroprotective effects of the neuregulin glial growth factor-2 on dopaminergic neurons in rat primary midbrain cultures. J Neurochem 91(6):1358–1368PubMedCrossRefGoogle Scholar
  13. 13.
    Ricart K, Pearson RJ, Viera L, Cassina P, Kamaid A, Carroll SL, Estevez AG (2006) Interactions between beta-neuregulin and neurotrophins in motor neuron apoptosis. J Neurochem 97(1):222–233PubMedCrossRefGoogle Scholar
  14. 14.
    Ryu J, Yu HN, Cho H, Kim HS, Baik TK, Lee SJ, Woo RS (2012) Neuregulin-1 exerts protective effects against neurotoxicities induced by C-terminal fragments of APP via ErbB4 receptor. J Pharmacol Sci 119(1):73–81PubMedCrossRefGoogle Scholar
  15. 15.
    Woo RS, Lee JH, Kim HS, Baek CH, Song DY, Suh YH, Baik TK (2012) Neuregulin-1 protects against neurotoxicities induced by Swedish amyloid precursor protein via the ErbB4 receptor. Neuroscience 202:413–423PubMedCrossRefGoogle Scholar
  16. 16.
    Carlsson T, Schindler FR, Hollerhage M, Depboylu C, Arias-Carrion O, Schnurrbusch S, Rosler TW, Wozny W, Schwall GP, Groebe K, Oertel WH, Brundin P, Schrattenholz A, Hoglinger GU (2011) Systemic administration of neuregulin-1beta1 protects dopaminergic neurons in a mouse model of Parkinson’s disease. J Neurochem 117(6):1066–1074PubMedCrossRefGoogle Scholar
  17. 17.
    Min SS, An J, Lee JH, Seol GH, Im JH, Kim HS, Baik TK, Woo RS (2011) Neuregulin-1 prevents amyloid beta-induced impairment of long-term potentiation in hippocampal slices via ErbB4. Neurosci Lett 505(1):6–9PubMedCrossRefGoogle Scholar
  18. 18.
    Guo WP, Fu XG, Jiang SM, Wu JZ (2010) Neuregulin-1 regulates the expression of Akt, Bcl-2, and Bad signaling after focal cerebral ischemia in rats. Biochem Cell Biol 88(4):649–654PubMedCrossRefGoogle Scholar
  19. 19.
    Guo WP, Wang J, Li RX, Peng YW (2006) Neuroprotective effects of neuregulin-1 in rat models of focal cerebral ischemia. Brain Res 1087(1):180–185PubMedCrossRefGoogle Scholar
  20. 20.
    Xu Z, Croslan DR, Harris AE, Ford GD, Ford BD (2006) Extended therapeutic window and functional recovery after intraarterial administration of neuregulin-1 after focal ischemic stroke. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 26(4):527–535CrossRefGoogle Scholar
  21. 21.
    Xu C, Lv L, Zheng G, Li B, Gao L, Sun Y (2012) Neuregulin1beta1 protects oligodendrocyte progenitor cells from oxygen glucose deprivation injury induced apoptosis via ErbB4-dependent activation of PI3-kinase/Akt. Brain Res 1467:104–112PubMedCrossRefGoogle Scholar
  22. 22.
    Liu S, Shen H, Xu M, Liu O, Zhao L, Guo Z, Du J (2010) FRP inhibits ox-LDL-induced endothelial cell apoptosis through an Akt-NF-{kappa}B-Bcl-2 pathway and inhibits endothelial cell apoptosis in an apoE-knockout mouse model. Am J Physiol Endocrinol Metab 299(3):E351–E363PubMedCrossRefGoogle Scholar
  23. 23.
    Liu Z, Gao W, Wang Y, Zhang W, Liu H, Li Z (2011) Neuregulin-1beta regulates outgrowth of neurites and migration of neurofilament 200 neurons from dorsal root ganglial explants in vitro. Peptides 32(6):1244–1248PubMedCrossRefGoogle Scholar
  24. 24.
    Sala G, Traini S, D’Egidio M, Vianale G, Rossi C, Piccolo E, Lattanzio R, Piantelli M, Tinari N, Natali PG, Muraro R, Iacobelli S (2012) An ErbB-3 antibody, MP-RM-1, inhibits tumor growth by blocking ligand-dependent and independent activation of ErbB-3/Akt signaling. Oncogene 31(10):1275–1286PubMedCrossRefGoogle Scholar
  25. 25.
    Xu X, Chua CC, Gao J, Chua KW, Wang H, Hamdy RC, Chua BH (2008) Neuroprotective effect of humanin on cerebral ischemia/reperfusion injury is mediated by a PI3 K/Akt pathway. Brain Res 1227:12–18PubMedCrossRefGoogle Scholar
  26. 26.
    Cui W, Sun Y, Wang Z, Xu C, Xu L, Wang F, Chen Z, Peng Y, Li R (2011) Activation of liver X receptor decreases BACE1 expression and activity by reducing membrane cholesterol levels. Neurochem Res 36(10):1910–1921PubMedCrossRefGoogle Scholar
  27. 27.
    Casal C, Serratosa J, Tusell JM (2004) Effects of beta-AP peptides on activation of the transcription factor NF-kappaB and in cell proliferation in glial cell cultures. Neurosci Res 48(3):315–323PubMedCrossRefGoogle Scholar
  28. 28.
    Chen G, Bower KA, Ma C, Fang S, Thiele CJ, Luo J (2004) Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamine-induced neuronal death. FASEB J Off Publ Fed Am Soc Exp Biol 18(10):1162–1164Google Scholar
  29. 29.
    Woo RS, Lee JH, Yu HN, Song DY, Baik TK (2011) Expression of ErbB4 in the neurons of Alzheimer’s disease brain and APP/PS1 mice, a model of Alzheimer’s disease. Anat Cell Biol 44(2):116–127PubMedCrossRefGoogle Scholar
  30. 30.
    Rosler TW, Depboylu C, Arias-Carrion O, Wozny W, Carlsson T, Hollerhage M, Oertel WH, Schrattenholz A, Hoglinger GU (2011) Biodistribution and brain permeability of the extracellular domain of neuregulin-1-beta1. Neuropharmacology 61(8):1413–1418PubMedCrossRefGoogle Scholar
  31. 31.
    Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430(7000):631–639PubMedCrossRefGoogle Scholar
  32. 32.
    Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13(2):159–170PubMedCrossRefGoogle Scholar
  33. 33.
    Pankonin MS, Sohi J, Kamholz J, Loeb JA (2009) Differential distribution of neuregulin in human brain and spinal fluid. Brain Res 1258:1–11PubMedCrossRefGoogle Scholar
  34. 34.
    Woo RS, Lee JH, Yu HN, Song DY, Baik TK (2010) Expression of ErbB4 in the apoptotic neurons of Alzheimer’s disease brain. Anat Cell Biol 43(4):332–339PubMedCrossRefGoogle Scholar
  35. 35.
    Tokita Y, Keino H, Matsui F, Aono S, Ishiguro H, Higashiyama S, Oohira A (2001) Regulation of neuregulin expression in the injured rat brain and cultured astrocytes. J Neurosci Off J Soc Neurosci 21(4):1257–1264Google Scholar
  36. 36.
    Calvo M, Zhu N, Tsantoulas C, Ma Z, Grist J, Loeb JA, Bennett DL (2010) Neuregulin-ErbB signaling promotes microglial proliferation and chemotaxis contributing to microgliosis and pain after peripheral nerve injury. J Neurosci Off J Soc Neurosc 30(15):5437–5450CrossRefGoogle Scholar
  37. 37.
    Tan GH, Liu YY, Hu XL, Yin DM, Mei L, Xiong ZQ (2012) Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons. Nat Neurosci 15(2):258–266CrossRefGoogle Scholar
  38. 38.
    Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 74(4):609–619PubMedCrossRefGoogle Scholar
  39. 39.
    Mahar I, Tan S, Davoli MA, Dominguez-Lopez S, Qiang C, Rachalski A, Turecki G, Mechawar N (2011) Subchronic peripheral neuregulin-1 increases ventral hippocampal neurogenesis and induces antidepressant-like effects. PLoS One 6(10):e26610PubMedCrossRefGoogle Scholar
  40. 40.
    Li Y, Lein PJ, Liu C, Bruun DA, Giulivi C, Ford GD, Tewolde T, Ross-Inta C, Ford BD (2012) Neuregulin-1 is neuroprotective in a rat model of organophosphate-induced delayed neuronal injury. Toxicol Appl Pharmacol 262(2):194–204PubMedCrossRefGoogle Scholar
  41. 41.
    Chaudhury AR, Gerecke KM, Wyss JM, Morgan DG, Gordon MN, Carroll SL (2003) Neuregulin-1 and erbB4 immunoreactivity is associated with neuritic plaques in Alzheimer disease brain and in a transgenic model of Alzheimer disease. J Neuropathol Exp Neurol 62(1):42–54PubMedGoogle Scholar
  42. 42.
    Safa RN, Peng XY, Pentassuglia L, Lim CC, Lamparter M, Silverstein C, Walker J, Chen B, Geisberg C, Hatzopoulos AK, Sawyer DB (2011) Neuregulin-1{beta} regulation of embryonic endothelial progenitor cell survival. Am J Physiol Heart Circ Physiol 300(4):H1311–H1319PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Weigang Cui
    • 1
    • 2
  • Jing Tao
    • 1
  • Zhongping Wang
    • 2
    • 3
  • Mingxin Ren
    • 1
  • Yinghua Zhang
    • 1
    • 2
  • Yan Sun
    • 2
  • Yuwen Peng
    • 2
    • 4
  • Ruixi Li
    • 2
    • 4
  1. 1.Key Open Lab for Tissue Regeneration of Henan Universities, Department of Human AnatomyXinxiang Medical UniversityXinxiangChina
  2. 2.Department of Anatomy, Histology and Embryology, Shanghai Medical CollegeFudan UniversityShanghaiChina
  3. 3.Department of Microbiology and Immunology, School of Basic Medical SciencesJiujiang UniversityJiujiangChina
  4. 4.Department of Anatomy, Histology and Embryology, Shanghai Medical SchoolFudan UniversityShanghaiChina

Personalised recommendations