Neuroscience Bulletin

, Volume 30, Issue 2, pp 359–366 | Cite as

Tau hyperphosphorylation induces apoptotic escape and triggers neurodegeneration in Alzheimer’s disease



Since abnormal post-translational modifications or gene mutations of tau have been detected in over twenty neurodegenerative disorders, tau has attracted widespread interest as a target protein. Among its various post-translational modifications, phosphorylation is the most extensively studied. It is recognized that tau hyperphosphorylation is the root cause of neurodegeneration in Alzheimer’s disease (AD); however, it is not clear how it causes neurodegeneration. Based on the findings that tau hyperphosphorylation leads to the escape of neurons from acute apoptosis and simultaneously impairs the function of neurons, we have proposed that the nature of AD neurodegeneration is the consequence of aborted apoptosis induced by tau phosphorylation. Therefore, proper manipulation of tau hyperphosphorylation could be promising for arresting AD neurodegeneration. In this review, the neuroprotective and neurodegenerative effects of tau hyperphosphorylation and our thoughts regarding their relationship are presented.


Alzheimer’s disease microtubule-associated protein tau hyperphosphorylation apoptosis neurodegeneration 


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  1. [1]
    Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 1986, 261: 6084–6089.PubMedGoogle Scholar
  2. [2]
    Hu YK, Wang X, Li L, Du YH, Ye HT, Li CY. MicroRNA-98 induces an Alzheimer’s disease-like disturbance by targeting insulin-like growth factor 1. Neurosci Bull 2013, 29: 745–751.PubMedCrossRefGoogle Scholar
  3. [3]
    Wang JZ, Liu F. Microtubule-associated protein tau in development, degeneration and protection of neurons. Prog Neurobiol 2008, 85: 148–175.PubMedCrossRefGoogle Scholar
  4. [4]
    Tian Q, Wang J. Role of serine/threonine protein phosphatase in Alzheimer’s disease. Neurosignals 2002, 11: 262–269.PubMedCrossRefGoogle Scholar
  5. [5]
    Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K. Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimers Dis 2013, 33Suppl 1: S123–139.PubMedGoogle Scholar
  6. [6]
    Wang JZ, Grundke-Iqbal I, Iqbal K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 2007, 25: 59–68.PubMedCentralPubMedCrossRefGoogle Scholar
  7. [7]
    Sun XJ, Zhao L, Zhao N, Pan XL, Fei GQ, Jin LR, et al. Benfotiamine prevents increased beta-amyloid production in HEK cells induced by high glucose. Neurosci Bull 2012, 28: 561–566.PubMedCrossRefGoogle Scholar
  8. [8]
    Zhu LQ, Wang SH, Liu D, Yin YY, Tian Q, Wang XC, et al. Activation of glycogen synthase kinase-3 inhibits longterm potentiation with synapse-associated impairments. J Neurosci 2007, 27: 12211–12220.PubMedCrossRefGoogle Scholar
  9. [9]
    Zhu LQ, Liu D, Hu J, Cheng J, Wang SH, Wang Q, et al. GSK-3 beta inhibits presynaptic vesicle exocytosis by phosphorylating P/Q-type calcium channel and interrupting SNARE complex formation. J Neurosci 2010, 30: 3624–3633.PubMedCrossRefGoogle Scholar
  10. [10]
    Liu SJ, Zhang AH, Li HL, Wang Q, Deng HM, Netzer WJ, et al. 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 2003, 87: 1333–1344.PubMedCrossRefGoogle Scholar
  11. [11]
    Xiong YS, Wang DL, Tan L, Wang X, Chen LM, Gong CX, et al. Inhibition of glycogen synthase kinase-3 reverses tau hyperphosphorylation induced by pin1 down-regulation. CNS Neurol Disord Drug Targets 2013, 12: 436–443.PubMedCrossRefGoogle Scholar
  12. [12]
    Yin J, Liu YH, Xu YF, Zhang YJ, Chen JG, Shu BH, et al. Melatonin arrests peroxynitrite-induced tau hyperphosphorylation and the overactivation of protein kinases in rat brain. J Pineal Res 2006, 41: 124–129.PubMedCrossRefGoogle Scholar
  13. [13]
    Peng CX, Hu J, Liu D, Hong XP, Wu YY, Zhu LQ, et al. Disease-modified glycogen synthase kinase-3beta intervention by melatonin arrests the pathology and memory deficits in an Alzheimer’s animal model. Neurobiol Aging 2013, 34: 1555–1563.PubMedCrossRefGoogle Scholar
  14. [14]
    Zhang YJ, Xu YF, Liu YH, Yin J, Wang JZ. Nitric oxide induces tau hyperphosphorylation via glycogen synthase kinase-3beta activation. FEBS Lett 2005, 579: 6230–6236.PubMedCrossRefGoogle Scholar
  15. [15]
    Li XH, Du LL, Cheng XS, Jiang X, Zhang Y, Lv BL, et al. Glycation exacerbates the neuronal toxicity of beta-amyloid. Cell Death Dis 2013, 4: e673.PubMedCentralPubMedCrossRefGoogle Scholar
  16. [16]
    Li XH, Lv BL, Xie JZ, Liu J, Zhou XW, Wang JZ. AGEs induce Alzheimer-like tau pathology and memory deficit via RAGEmediated GSK-3 activation. Neurobiol Aging 2012, 33: 1400–1410.PubMedCrossRefGoogle Scholar
  17. [17]
    Liu YH, Wei W, Yin J, Liu GP, Wang Q, Cao FY, et al. Proteasome inhibition increases tau accumulation independent of phosphorylation. Neurobiol Aging 2009, 30: 1949–1961.PubMedCrossRefGoogle Scholar
  18. [18]
    Wang ZF, Li HL, Li XC, Zhang Q, Tian Q, Wang Q, et al. Effects of endogenous beta-amyloid overproduction on tau phosphorylation in cell culture. J Neurochem 2006, 98: 1167–1175.PubMedCrossRefGoogle Scholar
  19. [19]
    Liu SJ, Zhang JY, Li HL, Fang ZY, Wang Q, Deng HM, et al. Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain. J Biol Chem 2004, 279: 50078–50088.PubMedCrossRefGoogle Scholar
  20. [20]
    Hong XP, Peng CX, Wei W, Tian Q, Liu YH, Yao XQ, et al. Essential role of tau phosphorylation in adult hippocampal neurogenesis. Hippocampus 2010, 20: 1339–1349.PubMedCrossRefGoogle Scholar
  21. [21]
    Gong CX, Shaikh S, Wang JZ, Zaidi T, Grundke-Iqbal I, Iqbal K. Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J Neurochem 1995, 65: 732–738.PubMedCrossRefGoogle Scholar
  22. [22]
    Wang JZ, Gong CX, Zaidi T, Grundke-Iqbal I, Iqbal K. Dephosphorylation of Alzheimer paired helical filaments by protein phosphatase-2A and -2B. J Biol Chem 1995, 270: 4854–4860.PubMedCrossRefGoogle Scholar
  23. [23]
    Wang JZ, Grundke-Iqbal I, Iqbal K. Restoration of biological activity of Alzheimer abnormally phosphorylated tau by dephosphorylation with protein phosphatase-2A, -2B and -1. Brain Res Mol Brain Res 1996, 38: 200–208.PubMedCrossRefGoogle Scholar
  24. [24]
    Gong CX, Lidsky T, Wegiel J, Zuck L, Grundke-Iqbal I, Iqbal K. Phosphorylation of microtubule-associated protein tau is regulated by protein phosphatase 2A in mammalian brain. Implications for neurofibrillary degeneration in Alzheimer’s disease. J Biol Chem 2000, 275: 5535–5544.PubMedCrossRefGoogle Scholar
  25. [25]
    Sun L, Liu SY, Zhou XW, Wang XC, Liu R, Wang Q, et al. Inhibition of protein phosphatase 2A- and protein phosphatase 1-induced tau hyperphosphorylation and impairment of spatial memory retention in rats. Neuroscience 2003, 118: 1175–1182.PubMedCrossRefGoogle Scholar
  26. [26]
    Yang Y, Yang XF, Wang YP, Tian Q, Wang XC, Li HL, et al. Inhibition of protein phosphatases induces transport deficits and axonopathy. J Neurochem 2007, 102: 878–886.PubMedCrossRefGoogle Scholar
  27. [27]
    Xiong Y, Jing XP, Zhou XW, Wang XL, Yang Y, Sun XY, et al. Zinc induces protein phosphatase 2A inactivation and tau hyperphosphorylation through Src dependent PP2A (tyrosine 307) phosphorylation. Neurobiol Aging 2013, 34: 745–756.PubMedCrossRefGoogle Scholar
  28. [28]
    Yu G, Yan T, Feng Y, Liu X, Xia Y, Luo H, et al. Ser9 phosphorylation causes cytoplasmic detention of I2PP2A/SET in Alzheimer disease. Neurobiol Aging 2013, 34: 1748–1758.PubMedCrossRefGoogle Scholar
  29. [29]
    Chai GS, Jiang X, Ni ZF, Ma ZW, Xie AJ, Cheng XS, et al. Betaine attenuates Alzheimer-like pathological changes and memory deficits induced by homocysteine. J Neurochem 2013, 124: 388–396.PubMedCrossRefGoogle Scholar
  30. [30]
    Cheng XS, Zhao KP, Jiang X, Du LL, Li XH, Ma ZW, et al. Nmnat2 attenuates Tau phosphorylation through activation of PP2A. J Alzheimers Dis 2013, 36: 185–195.PubMedGoogle Scholar
  31. [31]
    Liu XP, Zheng HY, Qu M, Zhang Y, Cao FY, Wang Q, et al. Upregulation of astrocytes protein phosphatase-2A stimulates astrocytes migration via inhibiting p38 MAPK in tg2576 mice. Glia 2012, 60: 1279–1288.PubMedCrossRefGoogle Scholar
  32. [32]
    Yao XQ, Zhang XX, Yin YY, Liu B, Luo DJ, Liu D, et al. Glycogen synthase kinase-3beta regulates Tyr307 phosphorylation of protein phosphatase-2A via protein tyrosine phosphatase 1B but not Src. Biochem J 2011, 437: 335–344.PubMedCrossRefGoogle Scholar
  33. [33]
    Liu GP, Zhang Y, Yao XQ, Zhang CE, Fang J, Wang Q, et al. Activation of glycogen synthase kinase-3 inhibits protein phosphatase-2A and the underlying mechanisms. Neurobiol Aging 2008, 29: 1348–1358.PubMedCrossRefGoogle Scholar
  34. [34]
    Wang JZ, Grundke-Iqbal I, Iqbal K. Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer’s disease. Nat Med 1996, 2: 871–875.PubMedCrossRefGoogle Scholar
  35. [35]
    Li X, Lu F, Wang JZ, Gong CX. Concurrent alterations of O-GlcNAcylation and phosphorylation of tau in mouse brains during fasting. Eur J Neurosci 2006, 23: 2078–2086.PubMedCrossRefGoogle Scholar
  36. [36]
    Han J, Wang XF, Yao HI, Gao C, Li F, Zhang BY, et al. Prion protein inhibits tau-mediated microtubule formation. Neurosci Bull. 2005, 21(6): 398–403.Google Scholar
  37. [37]
    Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci U S A 1994, 91: 5562–5566.PubMedCentralPubMedCrossRefGoogle Scholar
  38. [38]
    Wang JZ, Wu Q, Smith A, Grundke-Iqbal I, Iqbal K. Tau is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase. FEBS Lett 1998, 436: 28–34.PubMedCrossRefGoogle Scholar
  39. [39]
    Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci U S A 2001, 98: 6923–6928.PubMedCentralPubMedCrossRefGoogle Scholar
  40. [40]
    Salehi A, Delcroix JD, Mobley WC. Traffic at the intersection of neurotrophic factor signaling and neurodegeneration. Trends Neurosci 2003, 26: 73–80.PubMedCrossRefGoogle Scholar
  41. [41]
    Xiao AW, He J, Wang Q, Luo Y, Sun Y, Zhou YP, et al. The origin and development of plaques and phosphorylated tau are associated with axonopathy in Alzheimer’s disease. Neurosci Bull 2011, 27: 287–299.PubMedCrossRefGoogle Scholar
  42. [42]
    Spittaels K, Van den Haute C, Van Dorpe J, Bruynseels K, Vandezande K, Laenen I, et al. Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am J Pathol 1999, 155: 2153–2165.PubMedCentralPubMedCrossRefGoogle Scholar
  43. [43]
    Jackson GR, Wiedau-Pazos M, Sang TK, Wagle N, Brown CA, Massachi S, et al. Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron 2002, 34: 509–519.PubMedCrossRefGoogle Scholar
  44. [44]
    Perez M, Hernandez F, Lim F, Diaz-Nido J, Avila J. Chronic lithium treatment decreases mutant tau protein aggregation in a transgenic mouse model. J Alzheimers Dis 2003, 5: 301–308.PubMedGoogle Scholar
  45. [45]
    Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, et al. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A 2005, 102: 6990–6995.PubMedCentralPubMedCrossRefGoogle Scholar
  46. [46]
    Mori H, Kondo J, Ihara Y. Ubiquitin is a component of paired helical filaments in Alzheimer’s disease. Science 1987, 235: 1641–1644.PubMedCrossRefGoogle Scholar
  47. [47]
    Ren QG, Liao XM, Wang ZF, Qu ZS, Wang JZ. The involvement of glycogen synthase kinase-3 and protein phosphatase-2A in lactacystin-induced tau accumulation. FEBS Lett 2006, 580: 2503–2511.PubMedCrossRefGoogle Scholar
  48. [48]
    Ren QG, Liao XM, Chen XQ, Liu GP, Wang JZ. Effects of tau phosphorylation on proteasome activity. FEBS Lett 2007, 581: 1521–1528.PubMedCrossRefGoogle Scholar
  49. [49]
    Keck S, Nitsch R, Grune T, Ullrich O. Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer’s disease. J Neurochem 2003, 85: 115–122.PubMedCrossRefGoogle Scholar
  50. [50]
    Morsch R, Simon W, Coleman PD. Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol 1999, 58: 188–197.PubMedCrossRefGoogle Scholar
  51. [51]
    Spires TL, Orne JD, SantaCruz K, Pitstick R, Carlson GA, Ashe KH, et al. Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. Am J Pathol 2006, 168: 1598–1607.PubMedCentralPubMedCrossRefGoogle Scholar
  52. [52]
    Allen B, Ingram E, Takao M, Smith MJ, Jakes R, Virdee K, et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 2002, 22: 9340–9351.PubMedGoogle Scholar
  53. [53]
    Arendt T, Stieler J, Strijkstra AM, Hut RA, Rudiger J, Van der Zee EA, et al. Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci 2003, 23: 6972–6981.PubMedGoogle Scholar
  54. [54]
    Zhou F, Zhu X, Castellani RJ, Stimmelmayr R, Perry G, Smith MA, et al. Hibernation, a model of neuroprotection. Am J Pathol 2001, 158: 2145–2151.PubMedCentralPubMedCrossRefGoogle Scholar
  55. [55]
    Zhang DL, Chen YQ, Jiang X, Ji TT, Mei B. Oxidative damage increased in presenilin1/presenilin2 conditional double knockout mice. Neurosci Bull 2009, 25: 131–137.PubMedCrossRefGoogle Scholar
  56. [56]
    Liu GP, Wei W, Zhou X, Zhang Y, Shi HH, Yin J, et al. I(2)(PP2A) regulates p53 and Akt correlatively and leads the neurons to abort apoptosis. Neurobiol Aging 2012, 33: 254–264.PubMedCrossRefGoogle Scholar
  57. [57]
    Li HL, Wang HH, Liu SJ, Deng YQ, Zhang YJ, Tian Q, et al. Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin, a mechanism involved in Alzheimer’s neurodegeneration. Proc Natl Acad Sci U S A 2007, 104: 3591–3596.PubMedCentralPubMedCrossRefGoogle Scholar
  58. [58]
    Wang ZF, Yin J, Zhang Y, Zhu LQ, Tian Q, Wang XC, et al. Overexpression of tau proteins antagonizes amyloid-beta-potentiated apoptosis through mitochondria-caspase-3 pathway in N2a cells. J Alzheimers Dis 2010, 20: 145–157.PubMedGoogle Scholar
  59. [59]
    Wang HH, Li HL, Liu R, Zhang Y, Liao K, Wang Q, et al. Tau overexpression inhibits cell apoptosis with the mechanisms involving multiple viability-related factors. J Alzheimers Dis 2010, 21: 167–179.PubMedGoogle Scholar
  60. [60]
    Liu XA, Liao K, Liu R, Wang HH, Zhang Y, Zhang Q, et al. Tau dephosphorylation potentiates apoptosis by mechanisms involving a failed dephosphorylation/activation of Bcl-2. J Alzheimers Dis 2010, 19: 953–962.PubMedGoogle Scholar
  61. [61]
    Gu XM, Huang HC, Jiang ZF. Mitochondrial dysfunction and cellular metabolic deficiency in Alzheimer’s disease. Neurosci Bull 2012, 28: 631–640.PubMedCrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of Pathology and Pathophysiology, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

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