Advertisement

Neurochemical Research

, Volume 36, Issue 8, pp 1329–1335 | Cite as

Tau Mediated Neurodegeneration: An Insight into Alzheimer’s Disease Pathology

  • M. ObulesuEmail author
  • R. Venu
  • R. Somashekhar
Overview

Abstract

Extracellular accumulations of Aβ, hyperphosphorylation of tau and intracellular neurofibrillary tangle formation have been the hallmarks of Alzheimer’s Disease (AD). Although tau and its phosphorylation play a pivotal role in the normal physiology yet its hyperphosphorylation has been a pathological manifestation in neurodegenerative disorders like AD. In this review physiology of tau, its phosphorylation, hyperphosphorylation with the intervention of various kinases, aggregation and formation of paired helical filaments has been discussed. A brief account of various animal models employed to study the pathological manifestation of tau in AD and therapeutic strategies streamlined to counter the tau induced pathology has been given. The reasons for the failure to have suitable animal model to study AD pathology and recent success in achieving this has been included. The role of caspase cascade in tau cleavage has been emphasized. The summary of current studies on tau and the need for future studies has been accentuated.

Keywords

Alzheimer’s disease Tauopathy Tau phosphorylation Animal model 

Notes

Acknowledgments

Authors sincerely thank Dr. Joseph, Chairman, Garden City Group of Institutions, Bangalore for his generous support.

References

  1. 1.
    Gotz J, Schild A, Hoerndli F et al (2004) Amyloid-induced neurofibrillary tangle formation in Alzheimer’s disease: insight from transgenic mouse and tissue-culture models. Int J Dev Neurosci 22:453–465PubMedCrossRefGoogle Scholar
  2. 2.
    Obulesu M, Rao DM, Shamasundar NM (2009) Studies on genomic DNA stability in aluminium maltolate treated aged New Zealand rabbit: relevance to the Alzheimer’s animal model. J Clin Med Res 1:212–218Google Scholar
  3. 3.
    Obulesu M, Rao DM (2010) Animal models of Alzheimer’s disease: an understanding of pathology and therapeutic avenues. Int J Neurosci 120:531–537PubMedCrossRefGoogle Scholar
  4. 4.
    Obulesu M, Rao DM (2010) DNA damage and impairment of DNA repair in Alzheimer’s disease. Int J Neurosci 120:397–403PubMedCrossRefGoogle Scholar
  5. 5.
    Maria Jose Metcalfe MS, Figueiredo-Pereira ME (2010) Relationship between tau pathology and neuroinflammation in Alzheimer’s disease. Mt Sinai Med J 77:50–58CrossRefGoogle Scholar
  6. 6.
    Suzuki K, Terry RD (1967) Fine structural localization of acidphosphatase in senile plaques in Alzheimer’s presenile dementia. Acta Neuropathol 8:276–284PubMedCrossRefGoogle Scholar
  7. 7.
    Praprotnik D, Smith MA, Richey PL et al (1996) Filament heterogeneity within the dystrophic neurites of senile plaques suggests blockage of fast axonal transport in Alzheimer’s disease. Acta Neuropathol 91:226–235PubMedCrossRefGoogle Scholar
  8. 8.
    Stokin GB, Goldstein LS (2006) Axonal transport and Alzheimer’s disease. Annu Rev Biochem 75:607–627PubMedCrossRefGoogle Scholar
  9. 9.
    Cowan CM, Chee F, Shepherd D et al (2010) Disruption of neuronal function by soluble hyperphosphorylated tau in a Drosophila model of tauopathy. Biochem Soc Trans 38:564–570PubMedCrossRefGoogle Scholar
  10. 10.
    Cleveland DW, Hwo SY, Kirschner MW (1977) Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. J Mol Biol 116:227–247PubMedCrossRefGoogle Scholar
  11. 11.
    Grundke-Iqbal I, Iqbal K, Quinlan M et al (1986) Microtubule-associated protein tau: a component of Alzheimer paired helical filaments. J Biol Chem 261:6084–6089PubMedGoogle Scholar
  12. 12.
    Grundke-Iqbal I, Iqbal K, Tung YC et al (1986) Abnormal phosphorylation of the microtubule-associated protein tau (τ) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917PubMedCrossRefGoogle Scholar
  13. 13.
    Bramblett GT, Goedert M, Jakes R et al (1993) Abnormal tau phosphorylation at Ser396 in Alzheimer’s disease recapitulates development and contributes to reduced microtubule binding. Neuron 10:1089–1099PubMedCrossRefGoogle Scholar
  14. 14.
    Goedert M, Spillantini MG, Potier MC et al (1989) Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J 8:393–399PubMedGoogle Scholar
  15. 15.
    Jaworski T, Dewachter I, Seymour CM et al (2010) Alzheimer’s disease: old problem, new views from transgenic and viral models. Biochim Biophys Acta 1802:808–818PubMedGoogle Scholar
  16. 16.
    Mandelkow E, von Bergen M, Biernat J et al (2007) Structural principles of tau and the paired helical filaments of Alzheimer’s disease. Brain Pathol 17:83–90PubMedCrossRefGoogle Scholar
  17. 17.
    Rosenberg KJ, Ross JL, Feinstein HE et al (2008) Complementary dimerization of microtubule-associated tau protein: implications for microtubule bundling and tau-mediated pathogenesis. Proc Natl Acad Sci U S A 105:7445–7450PubMedCrossRefGoogle Scholar
  18. 18.
    Weingarten MD, Lockwood AH, Hwo SY et al (1975) A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 72:1858–1862PubMedCrossRefGoogle Scholar
  19. 19.
    Medeiros R, Baglietto-Vargas D, Laferla FM (2010) The role of tau in Alzheimer’s disease and related disorders. CNS Neurosci Ther (in press)Google Scholar
  20. 20.
    Li HL, Wang HH, Liu SJ et al (2007) Phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin: a mechanism involved in Alzheimer’s neurodegeneration. Proc Natl Acad Sci U S A 104:3591–3596PubMedCrossRefGoogle Scholar
  21. 21.
    Gomez-Ramos A, Smith MA, Perry G et al (2004) Tau phosphorylation and assembly. Acta Neurobiol Exp (Wars) 64:33–39Google Scholar
  22. 22.
    Johnson GV, Stoothoff WH (2004) Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci 117:5721–5729PubMedCrossRefGoogle Scholar
  23. 23.
    Tian Q, Wang J (2002) Role of serine/threonine protein phosphatase in Alzheimer’s disease. Neurosignals 11:262–269PubMedCrossRefGoogle Scholar
  24. 24.
    Iqbal K, Grundke-Iqbal I, Zaidi T et al (1986) Defective brain microtubule assembly in Alzheimer’s disease. Lancet 2:421–426PubMedCrossRefGoogle Scholar
  25. 25.
    Kopke E, Tung YC, Shaikh S et al (1993) Microtubule-associated protein tau: abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem 268:24374–24384PubMedGoogle Scholar
  26. 26.
    Sengupta A, Kabat J, Novak M et al (1998) Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch Biochem Biophys 357:299–309PubMedCrossRefGoogle Scholar
  27. 27.
    Wang JZ, Grundke-Iqbal I, Iqbal K (2007) Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci 25:59–68PubMedCrossRefGoogle Scholar
  28. 28.
    Diaz-Hernandez M, Gomez-Ramos A, Rubio A et al (2010) Tissue non-specific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau. J Biol Chem 285:32539–32548PubMedCrossRefGoogle Scholar
  29. 29.
    Gamblin TC, Chen F, Zambrano A et al (2003) Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci U S A 100:10032–10037PubMedCrossRefGoogle Scholar
  30. 30.
    Eckert A, Keil U, Marques CA et al (2003) Mitochondrial dysfunction, apoptotic cell death, and Alzheimer’s disease. Biochem Pharmacol 66:1627–1634PubMedCrossRefGoogle Scholar
  31. 31.
    Rissman RA, Poon WW, Blurton-Jones M et al (2004) Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest 114:121–130PubMedGoogle Scholar
  32. 32.
    Guillozet-Bongaarts AL, Cahill ME, Cryns VL et al (2006) Seudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo. J Neurochem 97:1005–1014PubMedCrossRefGoogle Scholar
  33. 33.
    Rohn TT, Rissman RA, Davis MC et al (2002) Caspase-9 activation and caspase cleavage of tau in the Alzheimer’s disease brain. Neurobiol Dis 11:341–354PubMedCrossRefGoogle Scholar
  34. 34.
    Rapoport M, Dawson HN, Binder LI et al (2002) Tau is essential to beta-amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A 99:6364–6369PubMedCrossRefGoogle Scholar
  35. 35.
    Yoshiyama Y, Higuchi M, Zhang B et al (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351PubMedCrossRefGoogle Scholar
  36. 36.
    Arnaud L, Robakis NK, Figueiredo-Pereira ME (2006) It may take inflammation, phosphorylation and ubiquitination to ‘tangle’ in Alzheimer’s disease. Neurodegener Dis 3:313–319PubMedCrossRefGoogle Scholar
  37. 37.
    Wang Y, Martinez-Vicente M, Kruger U et al (2009) Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet 18:4153–4170PubMedCrossRefGoogle Scholar
  38. 38.
    Li L, Zhang X, Le W (2010) Autophagy dysfunction in Alzheimer’s disease. Neurodegener Dis 7:265–271PubMedGoogle Scholar
  39. 39.
    Oddo S, Billings L, Kesslak JP et al (2004) Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43:321–332PubMedCrossRefGoogle Scholar
  40. 40.
    Kitazawa M, Oddo S, Yamasaki TR et al (2005) Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J Neurosci 25:8843–8853PubMedCrossRefGoogle Scholar
  41. 41.
    Caccamo A, Oddo S, Billings LM et al (2006) M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron 49:671–682PubMedCrossRefGoogle Scholar
  42. 42.
    Gong CX, Liu F, Grundke-Iqbal I et al (2006) Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. J Alzheimers Dis 9:1–12PubMedGoogle Scholar
  43. 43.
    Liu F, Shi J, Tanimukai H et al (2009) Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer’s disease. Brain 132:1820–1832PubMedCrossRefGoogle Scholar
  44. 44.
    Fonseca MI, Ager RR, Chu SH et al (2009) Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer’s disease. J Immunol 183:1375–1383PubMedCrossRefGoogle Scholar
  45. 45.
    Narayanan RL, Dur UH, Bibow S et al (2010) Automatic assignment of the intrinsically disordered protein tau with 441-residues. J Am Chem Soc 132:11906–11907PubMedCrossRefGoogle Scholar
  46. 46.
    Maccioni RB, Farias G, Morales I et al (2010) The revitalized tau hypothesis on Alzheimer’s disease. Arch Med Res 41:226–231PubMedCrossRefGoogle Scholar
  47. 47.
    Souter S, Lee G (2010) Tubulin-independent tau in Alzheimer’s disease and cancer: implications for disease pathogenesis and treatment. Curr Alzheimer Res 7:697–707PubMedCrossRefGoogle Scholar
  48. 48.
    Dolan PJ, Johnson GV (2010) A caspase cleaved form of tau is preferentially degraded through the autophagy pathway. J Biol Chem 285:21978–21987PubMedCrossRefGoogle Scholar
  49. 49.
    Wang HH, Li HL, Liu R et al (2010) Tau overexpression inhibits cell apoptosis with the mechanisms involving multiple viability-related factors. J Alzheimers Dis 21:167–179PubMedCrossRefGoogle Scholar
  50. 50.
    Ashe KH, Zahs KR (2010) Probing the biology of alzheimer’s disease in mice. Neuron 66:631–645PubMedCrossRefGoogle Scholar
  51. 51.
    Dawson HN, Ferreira A, Eyster MV et al (2001) Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci 114:1179–1187PubMedGoogle Scholar
  52. 52.
    Harada A, Oguchi K, Okabe S et al (1994) Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 369:488–491PubMedCrossRefGoogle Scholar
  53. 53.
    Boekhoorn K, Terwel D, Biemans B et al (2006) Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy. J Neurosci 26:3514–3523PubMedCrossRefGoogle Scholar
  54. 54.
    Ikegami S, Harada A, Hirokawa N (2000) Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice. Neurosci Lett 279:129–132PubMedCrossRefGoogle Scholar
  55. 55.
    Santacruz K, Lewis J, Spires T et al (2005) Tau suppression in a neurodegenerative mouse model improves memory function. Science 309:476–481PubMedCrossRefGoogle Scholar
  56. 56.
    Spires TL, Orne JD, SantaCruz K et al (2006) Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. Am J Pathol 168:1598–1607PubMedCrossRefGoogle Scholar
  57. 57.
    Go mez-Isla T, Hollister R, West H et al (1997) Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 41:17–24CrossRefGoogle Scholar
  58. 58.
    Andorfer C, Acker CM, Kress Y et al (2005) Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci 25:5446–5454PubMedCrossRefGoogle Scholar
  59. 59.
    Berger Z, Rode H, Hanna A et al (2007) Pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 27:3650–3662PubMedCrossRefGoogle Scholar
  60. 60.
    Rosenmann H, Grigoriadis N, Eldar-Levy H et al (2008) A novel transgenic mouse expressing double mutant tau driven by its natural promoter exhibits tauopathy characteristics. Exp Neurol 212:71–84PubMedCrossRefGoogle Scholar
  61. 61.
    Schindowski K, Bretteville A, Leroy K et al (2006) Alzheimer’s disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol 169:599–616PubMedCrossRefGoogle Scholar
  62. 62.
    Zilka N, Korenova M, Novak M (2009) Misfolded tau protein and disease modifying pathways in transgenic rodent models of human tauopathies. Acta Neuropathol 118:71–86PubMedCrossRefGoogle Scholar
  63. 63.
    Taes I, Goris A, Lemmens R et al (2010) Tau levels do not influence human ALS or motor neuron degeneration in the SOD1G93A mouse. Neurology 74:1687–1693PubMedCrossRefGoogle Scholar
  64. 64.
    Mudher A, Shepherd D, Newman TA et al (2004) GSK-3β inhibition reverses axonal transport defects and behavioural phenotypes in Drosophila. Mol Psychiatry 9:522–530PubMedCrossRefGoogle Scholar
  65. 65.
    Williams DW, Tyrer M, Shepherd D (2000) Tau and tau reporters disrupt central projections of sensory neurons in Drosophila. J Comp Neurol 428:630–640PubMedCrossRefGoogle Scholar
  66. 66.
    Wittmann CW, Wszolek MF, Shulman JM et al (2001) Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293:711–714PubMedCrossRefGoogle Scholar
  67. 67.
    Muyllaert D, Terwel D, Borghgraef P et al (2006) Transgenic mouse models for Alzheimer’s disease: the role of GSK-3ß in combined amyloid and tau-pathology. Rev Neurol (Paris) 162:903–907Google Scholar
  68. 68.
    Terwel D, Muyllaert D, Dewachter I et al (2008) Amyloid activates GSK-3β to aggravate neuronal tauopathy in bigenicmice. Am J Pathol 172:786–798PubMedCrossRefGoogle Scholar
  69. 69.
    Lewis J, McGowan E, Rockwood J et al (2000) Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet 25:402–405PubMedCrossRefGoogle Scholar
  70. 70.
    Lewis J, Dickson DW, Lin WL et al (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–1491PubMedCrossRefGoogle Scholar
  71. 71.
    Van Dorpe J, Smeijers I, Dewachter I et al (2000) Prominent cerebral amyloid angiopathy in transgenic mice overexpressing the London mutant of human APPin neurons. Am J Pathol 157:1283–1298PubMedCrossRefGoogle Scholar
  72. 72.
    Moechars D, Dewachter I, Lorent K et al (1999) Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem 274:6483–6492PubMedCrossRefGoogle Scholar
  73. 73.
    Osinde M, Clavaguera F, May-Nass R et al (2008) Lentivirus tau (P301S) expression in adult amyloid precursor protein (APP)-transgenic mice leads to tangle formation. Neuropathol Appl Neurobiol 24:523–531CrossRefGoogle Scholar
  74. 74.
    Dubois B, Feldman HH, Jacova C et al (2007) Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 6:734–746PubMedCrossRefGoogle Scholar
  75. 75.
    Foster TC (2007) Calcium homeostasis and modulation of synaptic plasticity in the aged brain. Aging Cell 6:319–325PubMedCrossRefGoogle Scholar
  76. 76.
    Skoulakis EM, Mudher A (2010) Two days of tau: a meeting focused on its biology and pathology. Biochem Soc Trans 38:953–954PubMedCrossRefGoogle Scholar
  77. 77.
    Kurz A, Perneczky R (2010) Novel insights for the treatment of Alzheimer’s disease. Prog Neuropsychopharmacol Biol Psychiatry 35:373–379PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of BiotechnologyRayalaseema UniversityKurnoolIndia
  2. 2.Department of Biotechnology, Capital CollegeGarden City Group of InstitutionsBangaloreIndia

Personalised recommendations