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Alzheimer’s pathogenesis: is there neuron-to-neuron propagation?

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Abstract

There is increasing interest in the early phase of Alzheimer’s disease before severe neuronal dysfunction occurs, but it is still not known when or where in the central nervous system the underlying pathological process begins. In this review, we discuss the idea of possible disease progression from the locus coeruleus to the transentorhinal region of the cerebral cortex via neuron-to-neuron transmission and transsynaptic transport of tau protein aggregates, and we speculate that such a mechanism together with the very long prodromal period that characterizes Alzheimer’s disease may be indicative of a prion-like pathogenesis for this tauopathy. The fact that AT8-immunoreactive abnormal tau aggregates (pretangles) develop within proximal axons of noradrenergic coeruleus projection neurons in the absence of both tau lesions (pretangles, NFTs/NTs) in the transentorhinal region as well as cortical amyloid-β pathology means that currently used neuropathological stages for Alzheimer’s disease will have to be reclassified.

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References

  1. Aguzzi A, Rajendran L (2009) The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron 64:783–790

    Article  PubMed  CAS  Google Scholar 

  2. Alafuzoff I, Arzberger T, Al-Sarraj S et al (2008) Staging of neurofibrillary pathology in Alzheimer’s disease: a study for the Brain Net Europe Consortium. Brain Pathol 18:484–496

    PubMed  Google Scholar 

  3. Alonso AC, Li B, Grundke-Iqbal I, Iqbal K (2008) Mechanism of tau-induced neurodegeneration in Alzheimer disease and related tauopathies. Curr Alzheimer Res 5:375–384

    Article  PubMed  CAS  Google Scholar 

  4. Amieva H, Le Goff M, Millet X et al (2008) Prodromal Alzheimer’s disease: successive emergence of clinical symptoms. Ann Neurol 64:492–498

    Article  PubMed  Google Scholar 

  5. Angot E, Steiner JA, Hansen C, Brundin P (2010) Are synucleinopathies prion-like disorders? Lancet Neurol 9:1128–1138

    Article  PubMed  Google Scholar 

  6. Arnold SE, Hyman BT, Flory J et al (1991) The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer’s disease. Cerebr Cortex 1:103–116

    Article  CAS  Google Scholar 

  7. Ballatore C, Lee VM, Trojanowski JQ (2007) Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8:663–672

    Article  PubMed  CAS  Google Scholar 

  8. Benarroch EE (2009) The locus coeruleus norepinephrine system. Neurology 73:1699–1704

    Article  PubMed  Google Scholar 

  9. Bobinski M, Wegiel J, Tarnawski M et al (1998) Duration of neurofibrillary changes in the hippocampal pyramidal neurons. Brain Res 799:156–158

    Article  PubMed  CAS  Google Scholar 

  10. Braak H, Braak E (1991) Neuropathological staging of Alzheimer-related changes. Acta Neuropathol 82:239–259

    Article  PubMed  CAS  Google Scholar 

  11. Braak H, Braak E (1997) Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 18:351–357

    Article  PubMed  CAS  Google Scholar 

  12. Braak E, Braak H, Mandelkow EM (1994) A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol 87:554–567

    Article  PubMed  CAS  Google Scholar 

  13. Braak H, Del Tredici K (2004) Alzheimer’s disease: intraneuronal alterations precede insoluble amyloid-β formation. Neurobiol Aging 25:713–718

    Article  PubMed  Google Scholar 

  14. Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121:171–181

    Article  PubMed  Google Scholar 

  15. Brundin P, Melki R, Kopito R (2010) Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol 11:301–307

    Article  PubMed  CAS  Google Scholar 

  16. Buée L, Bussiere T, Buée-Scherrer V et al (2003) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Rev 33:95–130

    Article  Google Scholar 

  17. Clavaguera F, Bolmont T, Crowther RA et al (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11:909–913

    Article  PubMed  CAS  Google Scholar 

  18. Cowan CM, Bossing T, Page A et al (2010) Soluble hyper-phosphorylated tau causes microtubule breakdown and functionally compromises normal tau in vivo. Acta Neuropathol 120:593–604

    Article  PubMed  CAS  Google Scholar 

  19. Cramer SC, Chopp M (2000) Recovery recapitulates ontogeny. Trends Neurosci 23:265–271

    Article  PubMed  CAS  Google Scholar 

  20. Davis DM, Sowinski S (2008) Membrane nanotubes: dynamic long-distance connections between animal cells. Nat Rev Mol Cell Biol 9:431–436

    Article  PubMed  CAS  Google Scholar 

  21. DeLacoste MC, White CL (1993) The role of cortical connectivity in Alzheimer’s disease pathogenesis: a review and model system. Neurobiol Aging 14:1–16

    Article  CAS  Google Scholar 

  22. Deramecourt V, Lebert F, Debachy B, Mackowiak-Cordoliani MA, Bombois S, Kerdraon O, Buée L, Maurage CA, Pasquier F (2010) Prediction of pathology in primary progressive language and speech disorders. Neurology 74:42–49

    Article  PubMed  CAS  Google Scholar 

  23. Desplats P, Lee H-J, Bae E-J et al (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. PNAS 106:13010–13015

    Article  PubMed  CAS  Google Scholar 

  24. Dickson DW, Braak H, Duda JE et al (2009) Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol 8:1150–1157

    Article  PubMed  CAS  Google Scholar 

  25. Duyckaerts C, Hauw JJ (1997) Prevalence, incidence and duration of Braak’s stages in the general population: can we know? Neurobiol Aging 18:362–369

    Article  PubMed  CAS  Google Scholar 

  26. Frautschy SA, Cole GM (2010) Why pleiotropic interventions are needed for Alzheimer’s disease. Mol Neurobiol 41:392–409

    Article  PubMed  CAS  Google Scholar 

  27. Frost B, Diamond MI (2010) The expanding realm of prion phenomena in neurodegenerative disease. Prion 3:74–77

    Article  Google Scholar 

  28. Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284:12845–12852

    Article  PubMed  CAS  Google Scholar 

  29. Frost B, Ollesch J, Wille H, Diamond MI (2009) Conformational diversity of wild-type tau fibrils specified by templated conformation change. J Biol Chem 284:3546–3551

    Article  PubMed  CAS  Google Scholar 

  30. German DC, Manaye KF, White CL 3rd (1992) Disease-specific patterns of locus coeruleus cell loss. Ann Neurol 32:667–676

    Article  PubMed  CAS  Google Scholar 

  31. Goedert M, Jakes R, Vandermeeren E (1995) Monoclonal antibody AT8 recognizes tau protein phosphorylated at serine 202 and threonine 205. Neurosci Lett 189:167–170

    Article  PubMed  CAS  Google Scholar 

  32. Goedert M, Clavaguera F, Tolnay M (2010) The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci 33:317–325

    Article  PubMed  CAS  Google Scholar 

  33. Goedert M, Klug A, Crowther RA (2006) Tau protein, the paired helical filament and Alzheimer’s disease. J Alzheimers Dis 9:195–207

    PubMed  CAS  Google Scholar 

  34. Gousset K, Zurzolo C (2008) Tunnelling nanotubes: a highway for prion spreading? Prion 3:94–98

    Article  Google Scholar 

  35. Grinberg LT, Rüb U, Ferretti RE et al (2009) The dorsal raphe nucleus shows phospho-tau neurofibrillary changes before the transentorhinal region in Alzheimer’s disease. A precocious onset? Neuropathol Appl Neurobiol 35:406–416

    Article  PubMed  CAS  Google Scholar 

  36. Grudzien A, Shaw P, Weintraub S et al (2007) Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging 28:327–335

    Article  PubMed  CAS  Google Scholar 

  37. Guo JL, Lee VM (2011) Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem. doi:10.1074/jbc.M110.209296

  38. Haglund M, Sjöbeck M, Englund E (2006) Locus ceruleus degeneration is ubiquitous in Alzheimer’s disease: possible implications for diagnosis and treatment. Neuropathology 26:528–532

    Article  PubMed  Google Scholar 

  39. Hansen C, Angot E, Bergström A-L et al (2011) α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 121:715–725

    Google Scholar 

  40. Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12:383–388

    Article  PubMed  CAS  Google Scholar 

  41. Hardy JA, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  PubMed  CAS  Google Scholar 

  42. Hyman BT (1998) New pathological criteria for Alzheimer’s disease. Arch Neurol 55:1174–1176

    Article  PubMed  CAS  Google Scholar 

  43. Iqbal K, Liu F, Gong CX et al (2009) Mechanisms of tau-induced neurodegeneration. Acta Neuropathol 118:53–69

    Article  PubMed  CAS  Google Scholar 

  44. Kertesz A, McMonagle P, Blair M, Davidson W, Munoz DG (2005) The evolution and pathology of frontotemporal dementia. Brain 128:1996–2005

    Article  PubMed  Google Scholar 

  45. Klein WL, Stine WB Jr, Teplow DB (2004) Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin in Alzheimer’s disease. Neurobiol Aging 25:569–580

    Article  PubMed  CAS  Google Scholar 

  46. Kovacech B, Skrabana R, Novak M (2010) Transition of tau protein from disordered to misordered in Alzheimer’s disease. Neurodegen Dis 7:24–27

    Article  CAS  Google Scholar 

  47. Li B, Chohan MO, Grundke-Iqbal I, Iqbal K (2007) Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tau. Acta Neuropathol 113:501–511

    Article  PubMed  CAS  Google Scholar 

  48. Li S, Shankar GM, Selkoe DJ (2010) How do soluble oligomers of amyloid beta-protein impair hippocampal synaptic plasticity? Front Cell Neurosci 4:5

    PubMed  Google Scholar 

  49. Lyness SA, Zarow C, Chui HC (2003) Neuron loss in key cholinergic and aminergic nuclei in Alzheimer’s disease: a meta-analysis. Neurobiol Aging 24:1–23

    Article  PubMed  CAS  Google Scholar 

  50. Mackenzie IRA, Neumann M, Bigio EH, Dickson DW et al (2010) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1–4

    Article  PubMed  Google Scholar 

  51. Mandelkow E, von Bergen M, Biernat J, Mandelkow EM (2007) Structural principles of tau and the paired helical filaments of Alzheimer’s disease. Brain Pathol 17:83–90

    Article  PubMed  CAS  Google Scholar 

  52. Mattson MP (2006) Molecular and cellular pathways towards and away from Alzheimer’s disease. In: Jucker M, Beyreuther K, Haass C, Nitsch R, Christen Y (eds) Alzheimer: 100 years and beyond. Springer, Berlin, pp 371–378

    Chapter  Google Scholar 

  53. Mattsson N, Sävman K, Osterlundh G et al (2010) Converging molecular pathways in human and neural development and degeneration. Neurosci Res 66:330–332

    Article  PubMed  CAS  Google Scholar 

  54. Mesulam MM (1998) From sensation to cognition. Brain 121:1013–1052

    Article  PubMed  Google Scholar 

  55. Moceri VM, Kukull WA, Emanuel I et al (2000) Early-life risk factors and the development of Alzheimer’s disease. Neurology 54:415–420

    PubMed  CAS  Google Scholar 

  56. Morsch R, Simon W, Coleman PD (1999) Neurons may live for decades with neurofibrillary tangles. J Neuropathol Exp Neurol 58:188–197

    Article  PubMed  CAS  Google Scholar 

  57. Neumann M (2009) Molecular neuropathology of TDP-43 proteinopathies. Int J Mol Sci 10:232–246

    Article  PubMed  CAS  Google Scholar 

  58. Olanow CW, Prusiner SB (2009) Is Parkinson’s disease a prion disorder? Proc Natl Acad Sci USA 106:12571–12572

    Article  PubMed  CAS  Google Scholar 

  59. Pan-Montojo F, Anichtchik O, Dening Y et al (2010) Progression of Parkinson’s disease pathology is reproduced by intragastric administration of rotenone in mice. PLoS One 5:38762

    Article  Google Scholar 

  60. Parvizi J, Van Hoesen GW, Damasio A (2001) The selective vulnerability of brainstem nuclei to Alzheimer’s disease. Ann Neurol 49:53–66

    Article  PubMed  CAS  Google Scholar 

  61. Pearson RCA (1996) Cortical connections and the pathology of Alzheimer’s disease. Neurodegeneration 5:429–434

    Article  PubMed  CAS  Google Scholar 

  62. Pimplikar SW (2009) Reassessing the amyloid cascade hypothesis of Alzheimer’s disease. Int J Biochem Cell Biol 41:1261–1268

    Article  PubMed  CAS  Google Scholar 

  63. Rockland KS, Pandya DN (1979) Laminar origins and terminations of cortical connections of the occipital lobe in the rhesus monkey. Brain Res 179:3–20

    Article  PubMed  CAS  Google Scholar 

  64. Saper CB, Wainer BH, German DC (1987) Axonal and transneuronal transport in the transmission of neurological disease: potential role in system degenerations, including Alzheimer’s disease. Neuroscience 23:389–398

    Article  PubMed  CAS  Google Scholar 

  65. Sara SJ (2009) The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 10:211–223

    Article  PubMed  CAS  Google Scholar 

  66. Schönheit B, Zarski R, Ohm TG (2004) Spatial and temporal relationships between plaques and tangles in Alzheimer-pathology. Neurobiol Aging 25:697–711

    Article  PubMed  Google Scholar 

  67. Selkoe DJ (1994) Alzheimer’s disease: a central role for amyloid. J Neuropathol Exp Neurol 53:438–447

    Article  PubMed  CAS  Google Scholar 

  68. Simic G, Stanic G, Mladinov M et al (2009) Does Alzheimer’s disease begin in the brainstem? Neuropathol Appl Neurobiol 35:532–554

    Article  PubMed  CAS  Google Scholar 

  69. Simons M, Raposo G (2009) Exosomes: vesicular carriers for intercellular communication. Curr Opin Cell Biol 21:575–581

    Article  PubMed  CAS  Google Scholar 

  70. Spires-Johnes TL, Stoothoff WH, de Calignon A et al (2009) Tau pathophysiology in neurodegeneration: a tangled issue. Trends Neurosci 32:150–159

    Article  Google Scholar 

  71. Stamer K, Vogel R, Thies E et al (2002) Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J Cell Biol 156:1051–1063

    Article  PubMed  CAS  Google Scholar 

  72. Teter B, Ashford JW (2002) Neuroplasticity in Alzheimer’s disease. J Neurosci Res 70:402–437

    Article  PubMed  CAS  Google Scholar 

  73. Thal DR, Rüb U, Orantes M, Braak H (2002) Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58:1791–1800

    PubMed  Google Scholar 

  74. Tsermentseli S, Leigh PN, Goldstein LH (2011) The anatomy of cognitive impairment in amyotrophic lateral sclerosis: More than frontal lobe dysfunction. Cortex (Epub ahead of print)

  75. Von Bartheld CS, Altick AL (2011) Multivesicular bodies in neurons: distribution, protein content, and trafficking functions. Prog Neurobiol 93:313–340

    Article  Google Scholar 

  76. Wegorzewska I, Bell S, Cairns NJ, Miller TM, Baloh RH (2009) TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci USA 106:18809–18814

    Article  PubMed  CAS  Google Scholar 

  77. Wilson AC, Dugger BN, Dickson DW, Wang DS (2011) TDP-43 in aging and Alzheimer’s disease—a review. Int J Clin Exp Pathol 4:147–155

    PubMed  CAS  Google Scholar 

  78. Wirths O, Multhaup G, Bayer TA (2004) A modified β-amyloid hypothesis: intraneuronal accumulation of the β-amyloid peptide—the first step of a fatal cascade. J Neurochem 91:513–520

    Article  PubMed  CAS  Google Scholar 

  79. Zarow C, Lyness SA, Mortimer JA, Chui HC (2003) Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 60:337–341

    Article  PubMed  Google Scholar 

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Acknowledgments

Both authors are supported by the Deutsche Forschungsgemeinschaft (Germany) Grant Number TR 1000/1-1 and the Michael J. Fox Foundation (New York, USA).

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Correspondence to Heiko Braak.

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For Kurt Jellinger in celebration of his 80th birthday.

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Braak, H., Del Tredici, K. Alzheimer’s pathogenesis: is there neuron-to-neuron propagation?. Acta Neuropathol 121, 589–595 (2011). https://doi.org/10.1007/s00401-011-0825-z

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