Skip to main content

Advertisement

SpringerLink
Log in

Protein coding of neurodegenerative dementias: the neuropathological basis of biomarker diagnostics

  • Review
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

Neuropathological diagnosis of neurodegenerative dementias evolved by adapting the results of neuroanatomy, biochemistry, and cellular and molecular biology. Milestone findings of intra- and extracellular argyrophilic structures, visualizing protein deposition, initiated a protein-based classification. Widespread application of immunohistochemical and biochemical investigations revealed that (1) there are modifications of proteins intrinsic to disease (species that are phosphorylated, nitrated, oligomers, proteinase-resistant, with or without amyloid characteristics; cleavage products), (2) disease forms characterized by the accumulation of a single protein only are rather the exception than the rule, and (3) some modifications of proteins elude present neuropathological diagnostic procedures. In this review, we summarize how neuropathology, together with biochemistry, contributes to disease typing, by demonstrating a spectrum of disorders characterized by the deposition of various modifications of various proteins in various locations. Neuropathology may help to elucidate how brain pathologies alter the detectability of proteins in body fluids by upregulation of physiological forms or entrapment of different proteins. Modifications of at least the five most relevant proteins (amyloid-β, prion protein, tau, α-synuclein, and TDP-43), aided by analysis of further “attracted” proteins, are pivotal to be evaluated simultaneously with different methods. This should complement the detection of biomarkers associated with pathogenetic processes, and also neuroimaging and genetic analysis, in order to obtain a highly personalized diagnostic profile. Defining clusters of patients based on the patterns of protein deposition and immunohistochemically or biochemically detectable modifications of proteins (“codes”) may have higher prognostic predictive value, may be useful for monitoring therapy, and may open new avenues for research on pathogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Alafuzoff I, Pikkarainen M, Al-Sarraj S et al (2006) Interlaboratory comparison of assessments of Alzheimer disease-related lesions: a study of the BrainNet Europe Consortium. J Neuropathol Exp Neurol 65:740–757

    CAS  PubMed  Google Scholar 

  2. Anderson JM, Hampton DW, Patani R et al (2008) Abnormally phosphorylated tau is associated with neuronal and axonal loss in experimental autoimmune encephalomyelitis and multiple sclerosis. Brain 131:1736–1748

    CAS  PubMed  Google Scholar 

  3. Anderson JM, Patani R, Reynolds R et al (2009) Evidence for abnormal tau phosphorylation in early aggressive multiple sclerosis. Acta Neuropathol 117:583–589

    CAS  PubMed  Google Scholar 

  4. Anderson JP, Walker DE, Goldstein JM et al (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J Biol Chem 281:29739–29752

    CAS  PubMed  Google Scholar 

  5. Andreadis A, Brown WM, Kosik KS (1992) Structure and novel exons of the human tau gene. Biochemistry 31:10626–10633

    CAS  PubMed  Google Scholar 

  6. Andringa G, Lam KY, Chegary M, Wang X, Chase TN, Bennett MC (2004) Tissue transglutaminase catalyzes the formation of alpha-synuclein crosslinks in Parkinson’s disease. FASEB J 18:932–934

    CAS  PubMed  Google Scholar 

  7. Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE (2006) Accelerated Tau deposition in the brains of individuals infected with human immunodeficiency virus-1 before and after the advent of highly active anti-retroviral therapy. Acta Neuropathol 111:529–538

    CAS  PubMed  Google Scholar 

  8. Arai T, Hasegawa M, Akiyama H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611

    CAS  PubMed  Google Scholar 

  9. Arai T, Mackenzie IR, Hasegawa M et al (2009) Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117:125–136

    CAS  PubMed  Google Scholar 

  10. Armstrong RA, Lantos PL, Cairns NJ (2005) Overlap between neurodegenerative disorders. Neuropathology 25:111–124

    PubMed  Google Scholar 

  11. Armstrong RA, Lantos PL, Cairns NJ (2008) What determines the molecular composition of abnormal protein aggregates in neurodegenerative disease? Neuropathology 28:351–365

    PubMed  Google Scholar 

  12. Bancher C, Brunner C, Lassmann H et al (1989) Tau and ubiquitin immunoreactivity at different stages of formation of Alzheimer neurofibrillary tangles. Prog Clin Biol Res 317:837–848

    CAS  PubMed  Google Scholar 

  13. Baskakov IV, Legname G, Baldwin MA, Prusiner SB, Cohen FE (2002) Pathway complexity of prion protein assembly into amyloid. J Biol Chem 277:21140–21148

    CAS  PubMed  Google Scholar 

  14. Beyer K, Domingo-Sabat M, Ariza A (2009) Molecular pathology of Lewy body diseases. Int J Mol Sci 10:724–745

    CAS  PubMed  Google Scholar 

  15. Beyer K, Domingo-Sabat M, Lao JI, Carrato C, Ferrer I, Ariza A (2008) Identification and characterization of a new alpha-synuclein isoform and its role in Lewy body diseases. Neurogenetics 9:15–23

    PubMed  Google Scholar 

  16. Bibl M, Mollenhauer B, Esselmann H et al (2006) CSF amyloid-beta-peptides in Alzheimer’s disease, dementia with Lewy bodies and Parkinson’s disease dementia. Brain 129:1177–1187

    PubMed  Google Scholar 

  17. Bibl M, Mollenhauer B, Lewczuk P et al (2007) Validation of amyloid-beta peptides in CSF diagnosis of neurodegenerative dementias. Mol Psychiatry 12:671–680

    CAS  PubMed  Google Scholar 

  18. Bigio EH, Lipton AM, Yen SH et al (2001) Frontal lobe dementia with novel tauopathy: sporadic multiple system tauopathy with dementia. J Neuropathol Exp Neurol 60:328–341

    CAS  PubMed  Google Scholar 

  19. Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F, Berry RW (2005) Tau, tangles, and Alzheimer’s disease. Biochim Biophys Acta 1739:216–223

    CAS  PubMed  Google Scholar 

  20. Borroni B, Malinverno M, Gardoni F et al (2008) Tau forms in CSF as a reliable biomarker for progressive supranuclear palsy. Neurology 71:1796–1803

    CAS  PubMed  Google Scholar 

  21. 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

    CAS  PubMed  Google Scholar 

  22. Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33:95–130

    CAS  PubMed  Google Scholar 

  23. Buee-Scherrer V, Buee L, Leveugle B et al (1997) Pathological tau proteins in postencephalitic parkinsonism: comparison with Alzheimer’s disease and other neurodegenerative disorders. Ann Neurol 42:356–359

    CAS  PubMed  Google Scholar 

  24. Cairns NJ, Bigio EH, Mackenzie IR et al (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:5–22

    PubMed  Google Scholar 

  25. Cairns NJ, Neumann M, Bigio EH et al (2007) TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 171:227–240

    CAS  PubMed  Google Scholar 

  26. Campbell BC, McLean CA, Culvenor JG et al (2001) The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson’s disease. J Neurochem 76:87–96

    CAS  PubMed  Google Scholar 

  27. Carrell RW, Lomas DA (1997) Conformational disease. Lancet 350:134–138

    CAS  PubMed  Google Scholar 

  28. Collinge J, Sidle KC, Meads J, Ironside J, Hill AF (1996) Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 383:685–690

    CAS  PubMed  Google Scholar 

  29. Cupidi C, Capobianco R, Goffredo D et al (2010) Neocortical Variation of Abeta Load in Fully Expressed, Pure Alzheimer’s Disease. J Alzheimers Dis 19:57–68

    PubMed  Google Scholar 

  30. Dalfo E, Martinez A, Muntane G, Ferrer I (2006) Abnormal alpha-synuclein solubility, aggregation and nitration in the frontal cortex in Pick’s disease. Neurosci Lett 400:125–129

    CAS  PubMed  Google Scholar 

  31. Danielson SR, Held JM, Schilling B, Oo M, Gibson BW, Andersen JK (2009) Preferentially increased nitration of alpha-synuclein at tyrosine-39 in a cellular oxidative model of Parkinson’s disease. Anal Chem 81:7823–7828

    CAS  PubMed  Google Scholar 

  32. Davidson Y, Amin H, Kelley T et al (2009) TDP-43 in ubiquitinated inclusions in the inferior olives in frontotemporal lobar degeneration and in other neurodegenerative diseases: a degenerative process distinct from normal ageing. Acta Neuropathol 118:359–369

    CAS  PubMed  Google Scholar 

  33. Debatin L, Streffer J, Geissen M, Matschke J, Aguzzi A, Glatzel M (2008) Association between deposition of beta-amyloid and pathological prion protein in sporadic Creutzfeldt-Jakob disease. Neurodegener Dis 5:347–354

    CAS  PubMed  Google Scholar 

  34. Derkinderen P, Scales TM, Hanger DP et al (2005) Tyrosine 394 is phosphorylated in Alzheimer’s paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase. J Neurosci 25:6584–6593

    CAS  PubMed  Google Scholar 

  35. Dickson DW (1999) Neuropathologic differentiation of progressive supranuclear palsy and corticobasal degeneration. J Neurol 246(Suppl 2):II6–II15

    PubMed  Google Scholar 

  36. Dickson DW, Fujishiro H, DelleDonne A et al (2008) Evidence that incidental Lewy body disease is pre-symptomatic Parkinson’s disease. Acta Neuropathol 115:437–444

    PubMed  Google Scholar 

  37. Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118:5–36

    CAS  PubMed  Google Scholar 

  38. Englund H, Degerman Gunnarsson M et al (2009) Oligomerization partially explains the lowering of Abeta42 in Alzheimer’s disease cerebrospinal fluid. Neurodegener Dis 6:139–147

    CAS  PubMed  Google Scholar 

  39. Feany MB, Mattiace LA, Dickson DW (1996) Neuropathologic overlap of progressive supranuclear palsy, Pick’s disease and corticobasal degeneration. J Neuropathol Exp Neurol 55:53–67

    CAS  PubMed  Google Scholar 

  40. Ferrer I, Blanco R, Carmona M et al (2001) Prion protein expression in senile plaques in Alzheimer’s disease. Acta Neuropathol 101:49–56

    CAS  PubMed  Google Scholar 

  41. Flament S, Delacourte A, Verny M, Hauw JJ, Javoy-Agid F (1991) Abnormal Tau proteins in progressive supranuclear palsy. Similarities and differences with the neurofibrillary degeneration of the Alzheimer type. Acta Neuropathol 81:591–596

    CAS  PubMed  Google Scholar 

  42. Foulds PG, Davidson Y, Mishra M et al (2009) Plasma phosphorylated-TDP-43 protein levels correlate with brain pathology in frontotemporal lobar degeneration. Acta Neuropathol 118(5):647–658

    Google Scholar 

  43. Frank S, Tolnay M (2009) Frontotemporal lobar degeneration: toward the end of conFUSion. Acta Neuropathol 118:629–631

    PubMed  Google Scholar 

  44. Freeman SH, Spires-Jones T, Hyman BT, Growdon JH, Frosch MP (2008) TAR-DNA binding protein 43 in Pick disease. J Neuropathol Exp Neurol 67:62–67

    CAS  PubMed  Google Scholar 

  45. Fujishiro H, Tsuboi Y, Lin WL, Uchikado H, Dickson DW (2008) Co-localization of tau and alpha-synuclein in the olfactory bulb in Alzheimer’s disease with amygdala Lewy bodies. Acta Neuropathol 116:17–24

    CAS  PubMed  Google Scholar 

  46. Fujishiro H, Uchikado H, Arai T et al (2009) Accumulation of phosphorylated TDP-43 in brains of patients with argyrophilic grain disease. Acta Neuropathol 117:151–158

    CAS  PubMed  Google Scholar 

  47. Fujita K, Ito H, Nakano S, Kinoshita Y, Wate R, Kusaka H (2008) Immunohistochemical identification of messenger RNA-related proteins in basophilic inclusions of adult-onset atypical motor neuron disease. Acta Neuropathol 116:439–445

    CAS  PubMed  Google Scholar 

  48. Fujiwara H, Hasegawa M, Dohmae N et al (2002) alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 4:160–164

    CAS  PubMed  Google Scholar 

  49. Gambetti P, Dong Z, Yuan J et al (2008) A novel human disease with abnormal prion protein sensitive to protease. Ann Neurol 63:697–708

    CAS  PubMed  Google Scholar 

  50. Geser F, Martinez-Lage M, Kwong LK, Lee VM, Trojanowski JQ (2009) Amyotrophic lateral sclerosis, frontotemporal dementia and beyond: the TDP-43 diseases. J Neurol 256:1205–1214

    PubMed  Google Scholar 

  51. Geser F, Martinez-Lage M, Robinson J et al (2009) Clinical and pathological continuum of multisystem TDP-43 proteinopathies. Arch Neurol 66:180–189

    PubMed  Google Scholar 

  52. Geser F, Winton MJ, Kwong LK et al (2008) Pathological TDP-43 in parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. Acta Neuropathol 115:133–145

    CAS  PubMed  Google Scholar 

  53. Ghetti B, Tagliavini F, Takao M, Bugiani O, Piccardo P (2003) Hereditary prion protein amyloidoses. Clin Lab Med 23:65–85 viii

    PubMed  Google Scholar 

  54. Giaccone G, Mangieri M, Capobianco R et al (2008) Tauopathy in human and experimental variant Creutzfeldt-Jakob disease. Neurobiol Aging 29:1864–1873

    CAS  PubMed  Google Scholar 

  55. Giaccone G, Marcon G, Mangieri M et al (2008) Atypical tauopathy with massive involvement of the white matter. Neuropathol Appl Neurobiol 34:468–472

    CAS  PubMed  Google Scholar 

  56. Giasson BI, Duda JE, Murray IV et al (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985–989

    CAS  PubMed  Google Scholar 

  57. Giasson BI, Lee VM, Trojanowski JQ (2003) Interactions of amyloidogenic proteins. Neuromolecular Med 4:49–58

    CAS  PubMed  Google Scholar 

  58. Goedert M, Jakes R, Crowther RA et al (1994) Epitope mapping of monoclonal antibodies to the paired helical filaments of Alzheimer’s disease: identification of phosphorylation sites in tau protein. Biochem J 301(Pt 3):871–877

    CAS  PubMed  Google Scholar 

  59. Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3:519–526

    CAS  PubMed  Google Scholar 

  60. Good PF, Werner P, Hsu A, Olanow CW, Perl DP (1996) Evidence of neuronal oxidative damage in Alzheimer’s disease. Am J Pathol 149:21–28

    CAS  PubMed  Google Scholar 

  61. Graeber MB (2009) Biomarkers for Parkinson’s disease. Exp Neurol 216:249–253

    CAS  PubMed  Google Scholar 

  62. Guillozet-Bongaarts AL, Glajch KE et al (2007) Phosphorylation and cleavage of tau in non-AD tauopathies. Acta Neuropathol 113:513–520

    CAS  PubMed  Google Scholar 

  63. Haik S, Privat N, Adjou KT et al (2002) Alpha-synuclein-immunoreactive deposits in human and animal prion diseases. Acta Neuropathol 103:516–520

    CAS  PubMed  Google Scholar 

  64. Hainfellner JA, Wanschitz J, Jellinger K, Liberski PP, Gullotta F, Budka H (1998) Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease. Acta Neuropathol 96:116–122

    CAS  PubMed  Google Scholar 

  65. Hanger DP, Anderton BH, Noble W (2009) Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. Trends Mol Med 15:112–119

    CAS  PubMed  Google Scholar 

  66. Hanger DP, Byers HL, Wray S et al (2007) Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J Biol Chem 282:23645–23654

    CAS  PubMed  Google Scholar 

  67. Hart GW (1997) Dynamic O-linked glycosylation of nuclear and cytoskeletal proteins. Annu Rev Biochem 66:315–335

    CAS  PubMed  Google Scholar 

  68. Hasegawa M, Arai T, Akiyama H et al (2007) TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. Brain 130:1386–1394

    PubMed  Google Scholar 

  69. Hasegawa M, Arai T, Nonaka T et al (2008) Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol 64:60–70

    CAS  PubMed  Google Scholar 

  70. He W, Barrow CJ (1999) The A beta 3-pyroglutamyl and 11-pyroglutamyl peptides found in senile plaque have greater beta-sheet forming and aggregation propensities in vitro than full-length A beta. Biochemistry 38:10871–10877

    CAS  PubMed  Google Scholar 

  71. Hensley K, Maidt ML, Yu Z, Sang H, Markesbery WR, Floyd RA (1998) Electrochemical analysis of protein nitrotyrosine and dityrosine in the Alzheimer brain indicates region-specific accumulation. J Neurosci 18:8126–8132

    CAS  PubMed  Google Scholar 

  72. Higashi S, Iseki E, Yamamoto R et al (2007) Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 1184:284–294

    CAS  PubMed  Google Scholar 

  73. Hill AF, Joiner S, Wadsworth JD et al (2003) Molecular classification of sporadic Creutzfeldt-Jakob disease. Brain 126:1333–1346

    PubMed  Google Scholar 

  74. Hishikawa N, Hashizume Y, Yoshida M, Niwa J, Tanaka F, Sobue G (2005) Tuft-shaped astrocytes in Lewy body disease. Acta Neuropathol 109:373–380

    PubMed  Google Scholar 

  75. Hodara R, Norris EH, Giasson BI et al (2004) Functional consequences of alpha-synuclein tyrosine nitration: diminished binding to lipid vesicles and increased fibril formation. J Biol Chem 279:47746–47753

    CAS  PubMed  Google Scholar 

  76. Hoffmann R, Lee VM, Leight S, Varga I, Otvos L Jr (1997) Unique Alzheimer’s disease paired helical filament specific epitopes involve double phosphorylation at specific sites. Biochemistry 36:8114–8124

    CAS  PubMed  Google Scholar 

  77. Horiguchi T, Uryu K, Giasson BI et al (2003) Nitration of tau protein is linked to neurodegeneration in tauopathies. Am J Pathol 163:1021–1031

    CAS  PubMed  Google Scholar 

  78. Horvath J, Kovari E, Bouras C, Burkhard PR (2009) Neuropathological correlates of lower limb corticobasal degeneration. Neuropathol Appl Neurobiol 35:623–627

    CAS  PubMed  Google Scholar 

  79. Hu WT, Josephs KA, Knopman DS et al (2008) Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease. Acta Neuropathol 116:215–220

    CAS  PubMed  Google Scholar 

  80. Ichihara K, Uchihara T, Nakamura A, Suzuki Y, Mizutani T (2009) Selective deposition of 4-repeat tau in cerebral infarcts. J Neuropathol Exp Neurol 68:1029–1036

    CAS  PubMed  Google Scholar 

  81. Igaz LM, Kwong LK, Xu Y et al (2008) Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am J Pathol 173:182–194

    CAS  PubMed  Google Scholar 

  82. Iqbal K, Flory M, Khatoon S et al (2005) Subgroups of Alzheimer’s disease based on cerebrospinal fluid molecular markers. Ann Neurol 58:748–757

    CAS  PubMed  Google Scholar 

  83. Isaacs AM, Powell C, Webb TE, Linehan JM, Collinge J, Brandner S (2008) Lack of TAR-DNA binding protein-43 (TDP-43) pathology in human prion diseases. Neuropathol Appl Neurobiol 34:446–456

    CAS  PubMed  Google Scholar 

  84. Iseki E, Marui W, Kosaka K, Ueda K (1999) Frequent coexistence of Lewy bodies and neurofibrillary tangles in the same neurons of patients with diffuse Lewy body disease. Neurosci Lett 265:9–12

    CAS  PubMed  Google Scholar 

  85. Iseki E, Togo T, Suzuki K et al (2003) Dementia with Lewy bodies from the perspective of tauopathy. Acta Neuropathol 105:265–270

    CAS  PubMed  Google Scholar 

  86. Ishizawa T, Mattila P, Davies P, Wang D, Dickson DW (2003) Colocalization of tau and alpha-synuclein epitopes in Lewy bodies. J Neuropathol Exp Neurol 62:389–397

    CAS  PubMed  Google Scholar 

  87. Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y (1994) Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13:45–53

    CAS  PubMed  Google Scholar 

  88. Iwatsubo T, Saido TC, Mann DM, Lee VM, Trojanowski JQ (1996) Full-length amyloid-beta (1–42(43)) and amino-terminally modified and truncated amyloid-beta 42(43) deposit in diffuse plaques. Am J Pathol 149:1823–1830

    CAS  PubMed  Google Scholar 

  89. Jellinger KA (2009) Absence of alpha-synuclein pathology in postencephalitic parkinsonism. Acta Neuropathol 118:371–379

    CAS  PubMed  Google Scholar 

  90. Jellinger KA (2009) Criteria for the neuropathological diagnosis of dementing disorders: routes out of the swamp? Acta Neuropathol 117:101–110

    PubMed  Google Scholar 

  91. Jellinger KA (2004) Lewy body-related alpha-synucleinopathy in the aged human brain. J Neural Transm 111:1219–1235

    CAS  PubMed  Google Scholar 

  92. Jellinger KA (2007) More frequent Lewy bodies but less frequent Alzheimer-type lesions in multiple system atrophy as compared to age-matched control brains. Acta Neuropathol 114:299–303

    PubMed  Google Scholar 

  93. Jellinger KA (2009) Recent advances in our understanding of neurodegeneration. J Neural Transm 116:1111–1162

    CAS  PubMed  Google Scholar 

  94. Jellinger KA, Attems J (2007) Neuropathological evaluation of mixed dementia. J Neurol Sci 257:80–87

    CAS  PubMed  Google Scholar 

  95. Jendroska K, Poewe W, Daniel SE et al (1995) Ischemic stress induces deposition of amyloid beta immunoreactivity in human brain. Acta Neuropathol 90:461–466

    CAS  PubMed  Google Scholar 

  96. Josephs KA, Katsuse O, Beccano-Kelly DA et al (2006) Atypical progressive supranuclear palsy with corticospinal tract degeneration. J Neuropathol Exp Neurol 65:396–405

    PubMed  Google Scholar 

  97. Josephs KA, Stroh A, Dugger B, Dickson DW (2009) Evaluation of subcortical pathology and clinical correlations in FTLD-U subtypes. Acta Neuropathol 118:349–358

    PubMed  Google Scholar 

  98. Josephs KA, Whitwell JL, Parisi JE et al (2008) Argyrophilic grains: a distinct disease or an additive pathology? Neurobiol Aging 29:566–573

    CAS  PubMed  Google Scholar 

  99. Junn E, Ronchetti RD, Quezado MM, Kim SY, Mouradian MM (2003) Tissue transglutaminase-induced aggregation of alpha-synuclein: Implications for Lewy body formation in Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 100:2047–2052

    CAS  PubMed  Google Scholar 

  100. Kadokura A, Yamazaki T, Lemere CA, Takatama M, Okamoto K (2009) Regional distribution of TDP-43 inclusions in Alzheimer disease (AD) brains: their relation to AD common pathology. Neuropathology 29:566–573

    PubMed  Google Scholar 

  101. Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK (2008) Striatal beta-amyloid deposition in Parkinson disease with dementia. J Neuropathol Exp Neurol 67:155–161

    PubMed  Google Scholar 

  102. Kalaitzakis ME, Pearce RK (2009) The morbid anatomy of dementia in Parkinson’s disease. Acta Neuropathol 118:587–598

    CAS  PubMed  Google Scholar 

  103. Kasai T, Tokuda T, Ishigami N et al (2009) Increased TDP-43 protein in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. Acta Neuropathol 117:55–62

    CAS  PubMed  Google Scholar 

  104. Kasai T, Tokuda T, Yamaguchi N et al (2008) Cleavage of normal and pathological forms of alpha-synuclein by neurosin in vitro. Neurosci Lett 436:52–56

    CAS  PubMed  Google Scholar 

  105. Kim EJ, Sung JY, Lee HJ et al (2006) Dyrk1A phosphorylates alpha-synuclein and enhances intracellular inclusion formation. J Biol Chem 281:33250–33257

    CAS  PubMed  Google Scholar 

  106. Kopke E, Tung YC, Shaikh S, Alonso AC, Iqbal K, Grundke-Iqbal I (1993) Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem 268:24374–24384

    CAS  PubMed  Google Scholar 

  107. Kovacs GG, Alafuzoff I, Al-Sarraj S et al (2008) Mixed brain pathologies in dementia: the BrainNet Europe consortium experience. Dement Geriatr Cogn Disord 26:343–350

    PubMed  Google Scholar 

  108. Kovacs GG, Budka H (2009) Molecular pathology of human prion diseases. Int J Mol Sci 10:976–999

    CAS  PubMed  Google Scholar 

  109. Kovacs GG, Budka H (2009) Protein-based neuropathology and molecular classification of human neurodegenerative diseases. In: Ovadi J, Orosz F (eds) Protein folding and misfolding: neurodegenerative diseases. Springer, the Netherlands, pp 251–272

  110. Kovacs GG, Gelpi E, Ströbel T et al (2007) Involvement of the endosomal-lysosomal system correlates with regional pathology in Creutzfeldt-Jakob disease. J Neuropathol Exp Neurol 66:628–636

    CAS  PubMed  Google Scholar 

  111. Kovacs GG, Majtenyi K, Spina S et al (2008) White matter tauopathy with globular glial inclusions: a distinct sporadic frontotemporal lobar degeneration. J Neuropathol Exp Neurol 67:963–975

    PubMed  Google Scholar 

  112. Kovacs GG, Milenkovic IJ, Preusser M, Budka H (2008) Nigral burden of alpha-synuclein correlates with striatal dopamine deficit. Mov Disord 23:1608–1612

    PubMed  Google Scholar 

  113. Kovacs GG, Zerbi P, Voigtlander T et al (2002) The prion protein in human neurodegenerative disorders. Neurosci Lett 329:269–272

    CAS  PubMed  Google Scholar 

  114. Kramer ML, Schulz-Schaeffer WJ (2007) Presynaptic alpha-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. J Neurosci 27:1405–1410

    CAS  PubMed  Google Scholar 

  115. Kuusisto E, Parkkinen L, Alafuzoff I (2003) Morphogenesis of Lewy bodies: dissimilar incorporation of alpha-synuclein, ubiquitin, and p62. J Neuropathol Exp Neurol 62:1241–1253

    CAS  PubMed  Google Scholar 

  116. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208

    CAS  PubMed  Google Scholar 

  117. Lambert MP, Barlow AK, Chromy BA et al (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95:6448–6453

    CAS  PubMed  Google Scholar 

  118. Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457:1128–1132

    CAS  PubMed  Google Scholar 

  119. Layfield R, Lowe J, Bedford L (2005) The ubiquitin-proteasome system and neurodegenerative disorders. Essays Biochem 41:157–171

    CAS  PubMed  Google Scholar 

  120. Lee G, Neve RL, Kosik KS (1989) The microtubule binding domain of tau protein. Neuron 2:1615–1624

    CAS  PubMed  Google Scholar 

  121. Lee G, Thangavel R, Sharma VM et al (2004) Phosphorylation of tau by fyn: implications for Alzheimer’s disease. J Neurosci 24:2304–2312

    CAS  PubMed  Google Scholar 

  122. Lee VM, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Annu Rev Neurosci 24:1121–1159

    CAS  PubMed  Google Scholar 

  123. Lefebvre T, Ferreira S, Dupont-Wallois L et al (2003) Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins—a role in nuclear localization. Biochim Biophys Acta 1619:167–176

    CAS  PubMed  Google Scholar 

  124. Leverenz JB, Umar I, Wang Q et al (2007) Proteomic identification of novel proteins in cortical Lewy bodies. Brain Pathol 17:139–145

    CAS  PubMed  Google Scholar 

  125. Lindboe CF, Hansen HB (1998) The frequency of Lewy bodies in a consecutive autopsy series. Clin Neuropathol 17:204–209

    CAS  PubMed  Google Scholar 

  126. Lindner H, Helliger W (2001) Age-dependent deamidation of asparagine residues in proteins. Exp Gerontol 36:1551–1563

    CAS  PubMed  Google Scholar 

  127. Liu CW, Giasson BI, Lewis KA, Lee VM, Demartino GN, Thomas PJ (2005) A precipitating role for truncated alpha-synuclein and the proteasome in alpha-synuclein aggregation: implications for pathogenesis of Parkinson disease. J Biol Chem 280:22670–22678

    CAS  PubMed  Google Scholar 

  128. Liu F, Iqbal K, Grundke-Iqbal I, Hart GW, Gong CX (2004) O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer’s disease. Proc Natl Acad Sci USA 101:10804–10809

    CAS  PubMed  Google Scholar 

  129. Lu JQ, Fan Y, Mitha AP, Bell R, Metz L, Moore GR, Yong VW (2009) Association of alpha-synuclein immunoreactivity with inflammatory activity in multiple sclerosis lesions. J Neuropathol Exp Neurol 68:179–189

    CAS  PubMed  Google Scholar 

  130. Luna-Munoz J, Chavez-Macias L, Garcia-Sierra F, Mena R (2007) Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer’s disease. J Alzheimers Dis 12:365–375

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  132. Markesbery WR, Schmitt FA, Kryscio RJ, Davis DG, Smith CD, Wekstein DR (2006) Neuropathologic substrate of mild cognitive impairment. Arch Neurol 63:38–46

    PubMed  Google Scholar 

  133. Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82:4245–4249

    CAS  PubMed  Google Scholar 

  134. Mateen FJ, Josephs KA (2009) TDP-43 is not present in brain tissue of patients with schizophrenia. Schizophr Res 108:297–298

    PubMed  Google Scholar 

  135. McKee AC, Cantu RC, Nowinski CJ et al (2009) Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J Neuropathol Exp Neurol 68:709–735

    PubMed  Google Scholar 

  136. Mena R, Edwards PC, Harrington CR, Mukaetova-Ladinska EB, Wischik CM (1996) Staging the pathological assembly of truncated tau protein into paired helical filaments in Alzheimer’s disease. Acta Neuropathol 91:633–641

    CAS  PubMed  Google Scholar 

  137. Meraz-Rios MA, Lira-De Leon KI, Campos-Pena V, De Anda-Hernandez MA, Mena-Lopez R (2009) Tau oligomers and aggregation in Alzheimer disease. J Neurochem. doi:JNC6511[pii]10.1111/j.1471-4159.2009.06511.x

  138. Meyne F, Gloeckner SF, Ciesielczyk B et al (2009) Total prion protein levels in the cerebrospinal fluid are reduced in patients with various neurological disorders. J Alzheimers Dis. doi:12G39G6736J3K264[pii]10.3233/JAD-2009-1110

  139. Miki Y, Mori F, Hori E, Kaimori M, Wakabayashi K (2009) Hippocampal sclerosis with four-repeat tau-positive round inclusions in the dentate gyrus: a new type of four-repeat tauopathy. Acta Neuropathol 117:713–718

    CAS  PubMed  Google Scholar 

  140. Mikolaenko I, Pletnikova O, Kawas CH et al (2005) Alpha-synuclein lesions in normal aging, Parkinson disease, and Alzheimer disease: evidence from the Baltimore Longitudinal Study of Aging (BLSA). J Neuropathol Exp Neurol 64:156–162

    CAS  PubMed  Google Scholar 

  141. Miller DW, Cookson MR, Dickson DW (2004) Glial cell inclusions and the pathogenesis of neurodegenerative diseases. Neuron Glia Biol 1:13–21

    PubMed  Google Scholar 

  142. Mondragon-Rodriguez S, Mena R, Binder LI, Smith MA, Perry G, Garcia-Sierra F (2008) Conformational changes and cleavage of tau in Pick bodies parallel the early processing of tau found in Alzheimer pathology. Neuropathol Appl Neurobiol 34:62–75

    CAS  PubMed  Google Scholar 

  143. Mori F, Hayashi S, Yamagishi S et al (2002) Pick’s disease: alpha- and beta-synuclein-immunoreactive Pick bodies in the dentate gyrus. Acta Neuropathol 104:455–461

    CAS  PubMed  Google Scholar 

  144. Morishima-Kawashima M, Hasegawa M, Takio K et al (1995) Proline-directed and non-proline-directed phosphorylation of PHF-tau. J Biol Chem 270:823–829

    CAS  PubMed  Google Scholar 

  145. Munoz DG, Neumann M, Kusaka H et al (2009) FUS pathology in basophilic inclusion body disease. Acta Neuropathol 118:617–627

    CAS  PubMed  Google Scholar 

  146. Muntane G, Dalfo E, Martinez A, Ferrer I (2008) Phosphorylation of tau and alpha-synuclein in synaptic-enriched fractions of the frontal cortex in Alzheimer’s disease, and in Parkinson’s disease and related alpha-synucleinopathies. Neuroscience 152:913–923

    CAS  PubMed  Google Scholar 

  147. Murray IV, Giasson BI, Quinn SM et al (2003) Role of alpha-synuclein carboxy-terminus on fibril formation in vitro. Biochemistry 42:8530–8540

    CAS  PubMed  Google Scholar 

  148. Nakamura T, Yamashita H, Takahashi T, Nakamura S (2001) Activated Fyn phosphorylates alpha-synuclein at tyrosine residue 125. Biochem Biophys Res Commun 280:1085–1092

    CAS  PubMed  Google Scholar 

  149. Nakashima-Yasuda H, Uryu K, Robinson J et al (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114:221–229

    CAS  PubMed  Google Scholar 

  150. Naslund J, Schierhorn A, Hellman U et al (1994) Relative abundance of Alzheimer A beta amyloid peptide variants in Alzheimer disease and normal aging. Proc Natl Acad Sci USA 91:8378–8382

    CAS  PubMed  Google Scholar 

  151. Negro A, Brunati AM, Donella-Deana A, Massimino ML, Pinna LA (2002) Multiple phosphorylation of alpha-synuclein by protein tyrosine kinase Syk prevents eosin-induced aggregation. FASEB J 16:210–212

    CAS  PubMed  Google Scholar 

  152. Nemes Z, Devreese B, Steinert PM, Van Beeumen J, Fesus L (2004) Cross-linking of ubiquitin, HSP27, parkin, and alpha-synuclein by gamma-glutamyl-epsilon-lysine bonds in Alzheimer’s neurofibrillary tangles. FASEB J 18:1135–1137

    CAS  PubMed  Google Scholar 

  153. Nemes Z, Petrovski G, Aerts M, Sergeant K, Devreese B, Fesus L (2009) Transglutaminase-mediated intramolecular cross-linking of membrane-bound alpha-synuclein promotes amyloid formation in Lewy bodies. J Biol Chem 284:27252–27264

    CAS  PubMed  Google Scholar 

  154. Neumann M, Kahle PJ, Giasson BI et al (2002) Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies. J Clin Invest 110:1429–1439

    CAS  PubMed  Google Scholar 

  155. Neumann M, Kwong LK, Lee EB et al (2009) Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol 117:137–149

    CAS  PubMed  Google Scholar 

  156. Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931

    PubMed  Google Scholar 

  157. Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie IR (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118:605–616

    CAS  PubMed  Google Scholar 

  158. Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133

    CAS  PubMed  Google Scholar 

  159. Neve RL, Harris P, Kosik KS, Kurnit DM, Donlon TA (1986) Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2. Brain Res 387:271–280

    CAS  PubMed  Google Scholar 

  160. Newman J, Rissman RA, Sarsoza F et al (2005) Caspase-cleaved tau accumulation in neurodegenerative diseases associated with tau and alpha-synuclein pathology. Acta Neuropathol 110:135–144

    CAS  PubMed  Google Scholar 

  161. Norlund MA, Lee JM, Zainelli GM, Muma NA (1999) Elevated transglutaminase-induced bonds in PHF tau in Alzheimer’s disease. Brain Res 851:154–163

    CAS  PubMed  Google Scholar 

  162. Obi K, Akiyama H, Kondo H et al (2008) Relationship of phosphorylated alpha-synuclein and tau accumulation to Abeta deposition in the cerebral cortex of dementia with Lewy bodies. Exp Neurol 210:409–420

    CAS  PubMed  Google Scholar 

  163. Ou SH, Wu F, Harrich D, Garcia-Martinez LF, Gaynor RB (1995) Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol 69:3584–3596

    CAS  PubMed  Google Scholar 

  164. Paleologou KE, Kragh CL, Mann DM et al (2009) Detection of elevated levels of soluble alpha-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain 132:1093–1101

    PubMed  Google Scholar 

  165. Paleologou KE, Schmid AW, Rospigliosi CC et al (2008) Phosphorylation at Ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of alpha-synuclein. J Biol Chem 283:16895–16905

    CAS  PubMed  Google Scholar 

  166. Papadopoulos D, Ewans L, Pham-Dinh D, Knott J, Reynolds R (2006) Upregulation of alpha-synuclein in neurons and glia in inflammatory demyelinating disease. Mol Cell Neurosci 31:597–612

    CAS  PubMed  Google Scholar 

  167. Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94:79–100

    CAS  PubMed  Google Scholar 

  168. Parchi P, Castellani R, Capellari S et al (1996) Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann Neurol 39:767–778

    CAS  PubMed  Google Scholar 

  169. Parchi P, Giese A, Capellari S et al (1999) Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 46:224–233

    CAS  PubMed  Google Scholar 

  170. Parchi P, Strammiello R, Notari S et al. (2009) Incidence and spectrum of sporadic Creutzfeldt-Jakob disease variants with mixed phenotype and co-occurrence of PrP(Sc) types: an updated classification. Acta Neuropathol 118:659–671

    Google Scholar 

  171. Parkin ET, Watt NT, Hussain I et al (2007) Cellular prion protein regulates beta-secretase cleavage of the Alzheimer’s amyloid precursor protein. Proc Natl Acad Sci USA 104:11062–11067

    CAS  PubMed  Google Scholar 

  172. Parkkinen L, Kauppinen T, Pirttila T, Autere JM, Alafuzoff I (2005) Alpha-synuclein pathology does not predict extrapyramidal symptoms or dementia. Ann Neurol 57:82–91

    CAS  PubMed  Google Scholar 

  173. Parkkinen L, Soininen H, Alafuzoff I (2003) Regional distribution of alpha-synuclein pathology in unimpaired aging and Alzheimer disease. J Neuropathol Exp Neurol 62:363–367

    CAS  PubMed  Google Scholar 

  174. Pennington C, Chohan G, Mackenzie J et al (2009) The role of cerebrospinal fluid proteins as early diagnostic markers for sporadic Creutzfeldt-Jakob disease. Neurosci Lett 455:56–59

    CAS  PubMed  Google Scholar 

  175. Petersen RC, Parisi JE, Dickson DW et al (2006) Neuropathologic features of amnestic mild cognitive impairment. Arch Neurol 63:665–672

    PubMed  Google Scholar 

  176. Piao YS, Tan CF, Iwanaga K et al (2005) Sporadic four-repeat tauopathy with frontotemporal degeneration, parkinsonism and motor neuron disease. Acta Neuropathol 110:600–609

    PubMed  Google Scholar 

  177. Popescu A, Lippa CF, Lee VM, Trojanowski JQ (2004) Lewy bodies in the amygdala: increase of alpha-synuclein aggregates in neurodegenerative diseases with tau-based inclusions. Arch Neurol 61:1915–1919

    PubMed  Google Scholar 

  178. Powers JM, Byrne NP, Ito M et al (2003) A novel leukoencephalopathy associated with tau deposits primarily in white matter glia. Acta Neuropathol 106:181–187

    CAS  PubMed  Google Scholar 

  179. Puig B, Rey MJ, Ferrer I (2005) Individual and regional variations of phospho-tau species in progressive supranuclear palsy. Acta Neuropathol 110:261–268

    CAS  PubMed  Google Scholar 

  180. Quilty MC, King AE, Gai WP et al (2006) Alpha-synuclein is upregulated in neurones in response to chronic oxidative stress and is associated with neuroprotection. Exp Neurol 199:249–256

    CAS  PubMed  Google Scholar 

  181. Ramasamy R, Vannucci SJ, Yan SS, Herold K, Yan SF, Schmidt AM (2005) Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. Glycobiology 15:16R–28R

    CAS  PubMed  Google Scholar 

  182. Ray S, Britschgi M, Herbert C et al (2007) Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat Med 13:1359–1362

    CAS  PubMed  Google Scholar 

  183. Reyes JF, Reynolds MR, Horowitz PM et al (2008) A possible link between astrocyte activation and tau nitration in Alzheimer’s disease. Neurobiol Dis 31:198–208

    CAS  PubMed  Google Scholar 

  184. Reynolds CH, Garwood CJ, Wray S et al (2008) Phosphorylation regulates tau interactions with Src homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cgamma1, Grb2, and Src family kinases. J Biol Chem 283:18177–18186

    CAS  PubMed  Google Scholar 

  185. Reynolds MR, Berry RW, Binder LI (2005) Site-specific nitration and oxidative dityrosine bridging of the tau protein by peroxynitrite: implications for Alzheimer’s disease. Biochemistry 44:1690–1700

    CAS  PubMed  Google Scholar 

  186. Reynolds MR, Reyes JF, Fu Y et al (2006) Tau nitration occurs at tyrosine 29 in the fibrillar lesions of Alzheimer’s disease and other tauopathies. J Neurosci 26:10636–10645

    CAS  PubMed  Google Scholar 

  187. Rhein V, Song X, Wiesner A et al (2009) Amyloid-beta and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer’s disease mice. Proc Natl Acad Sci USA 106:20057–20062

    CAS  PubMed  Google Scholar 

  188. Roher AE, Lowenson JD, Clarke S et al (1993) Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer’s disease. J Biol Chem 268:3072–3083

    CAS  PubMed  Google Scholar 

  189. Roher AE, Palmer KC, Yurewicz EC, Ball MJ, Greenberg BD (1993) Morphological and biochemical analyses of amyloid plaque core proteins purified from Alzheimer disease brain tissue. J Neurochem 61:1916–1926

    CAS  PubMed  Google Scholar 

  190. Safar J, Wille H, Itri V et al (1998) Eight prion strains have PrP(Sc) molecules with different conformations. Nat Med 4:1157–1165

    CAS  PubMed  Google Scholar 

  191. Saido TC, Yamao-Harigaya W, Iwatsubo T, Kawashima S (1996) Amino- and carboxyl-terminal heterogeneity of beta-amyloid peptides deposited in human brain. Neurosci Lett 215:173–176

    CAS  PubMed  Google Scholar 

  192. Saito Y, Kawashima A, Ruberu NN et al (2003) Accumulation of phosphorylated alpha-synuclein in aging human brain. J Neuropathol Exp Neurol 62:644–654

    CAS  PubMed  Google Scholar 

  193. Saito Y, Murayama S (2007) Neuropathology of mild cognitive impairment. Neuropathology 27:578–584

    PubMed  Google Scholar 

  194. Saito Y, Ruberu NN, Sawabe M et al (2004) Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol 63:911–918

    PubMed  Google Scholar 

  195. Santpere G, Ferrer I (2009) Delineation of early changes in cases with progressive supranuclear palsy-like pathology. Astrocytes in striatum are primary targets of tau phosphorylation and GFAP oxidation. Brain Pathol 19:177–187

    CAS  PubMed  Google Scholar 

  196. Schneider JA, Arvanitakis Z, Bang W, Bennett DA (2007) Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69:2197–2204

    PubMed  Google Scholar 

  197. Schneider JA, Arvanitakis Z, Leurgans SE, Bennett DA (2009) The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol 66:200–208

    PubMed  Google Scholar 

  198. Sergeant N, Bombois S, Ghestem A et al (2003) Truncated beta-amyloid peptide species in pre-clinical Alzheimer’s disease as new targets for the vaccination approach. J Neurochem 85:1581–1591

    CAS  PubMed  Google Scholar 

  199. Sergeant N, Delacourte A, Buee L (2005) Tau protein as a differential biomarker of tauopathies. Biochim Biophys Acta 1739:179–197

    CAS  PubMed  Google Scholar 

  200. Sergeant N, Wattez A, Delacourte A (1999) Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusively “exon 10” isoforms. J Neurochem 72:1243–1249

    CAS  PubMed  Google Scholar 

  201. Shaw LM, Korecka M, Clark CM, Lee VM, Trojanowski JQ (2007) Biomarkers of neurodegeneration for diagnosis and monitoring therapeutics. Nat Rev Drug Discov 6:295–303

    CAS  PubMed  Google Scholar 

  202. Shimizu H, Kakita A, Takahashi H (2008) Spinal cord tau pathology in cervical spondylotic myelopathy. Acta Neuropathol 115:185–192

    CAS  PubMed  Google Scholar 

  203. Shimura H, Schlossmacher MG, Hattori N et al (2001) Ubiquitination of a new form of alpha-synuclein by parkin from human brain: implications for Parkinson’s disease. Science 293:263–269

    CAS  PubMed  Google Scholar 

  204. Silveira-Moriyama L, Gonzalez AM, O’Sullivan SS et al (2009) Concomitant progressive supranuclear palsy and multiple system atrophy: more than a simple twist of fate? Neurosci Lett 467:208–211

    CAS  PubMed  Google Scholar 

  205. Singer SM, Zainelli GM, Norlund MA, Lee JM, Muma NA (2002) Transglutaminase bonds in neurofibrillary tangles and paired helical filament tau early in Alzheimer’s disease. Neurochem Int 40:17–30

    CAS  PubMed  Google Scholar 

  206. Smith MA, Richey Harris PL, Sayre LM, Beckman JS, Perry G (1997) Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J Neurosci 17:2653–2657

    CAS  PubMed  Google Scholar 

  207. Snow AD, Mar H, Nochlin D et al (1990) Early accumulation of heparan sulfate in neurons and in the beta-amyloid protein-containing lesions of Alzheimer’s disease and Down’s syndrome. Am J Pathol 137:1253–1270

    CAS  PubMed  Google Scholar 

  208. Song YJ, Halliday GM, Holton JL et al (2009) Degeneration in different parkinsonian syndromes relates to astrocyte type and astrocyte protein expression. J Neuropathol Exp Neurol 68:1073–1083

    CAS  PubMed  Google Scholar 

  209. Soto C, Estrada LD (2008) Protein misfolding and neurodegeneration. Arch Neurol 65:184–189

    PubMed  Google Scholar 

  210. Takahashi M, Tsujioka Y, Yamada T et al (1999) Glycosylation of microtubule-associated protein tau in Alzheimer’s disease brain. Acta Neuropathol 97:635–641

    CAS  PubMed  Google Scholar 

  211. Tan CF, Piao YS, Kakita A et al (2005) Frontotemporal dementia with co-occurrence of astrocytic plaques and tufted astrocytes, and severe degeneration of the cerebral white matter: a variant of corticobasal degeneration? Acta Neuropathol 109:329–338

    PubMed  Google Scholar 

  212. Tekirian TL, Saido TC, Markesbery WR et al (1998) N-terminal heterogeneity of parenchymal and cerebrovascular Abeta deposits. J Neuropathol Exp Neurol 57:76–94

    CAS  PubMed  Google Scholar 

  213. Thal DR, Ghebremedhin E, Rub U, Yamaguchi H, Del Tredici K, Braak H (2002) Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol 61:282–293

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  215. Tofaris GK, Razzaq A, Ghetti B, Lilley KS, Spillantini MG (2003) Ubiquitination of alpha-synuclein in Lewy bodies is a pathological event not associated with impairment of proteasome function. J Biol Chem 278:44405–44411

    CAS  PubMed  Google Scholar 

  216. Tolnay M, Clavaguera F (2004) Argyrophilic grain disease: a late-onset dementia with distinctive features among tauopathies. Neuropathology 24:269–283

    PubMed  Google Scholar 

  217. Trojanowski JQ, Lee VM (2000) “Fatal attractions” of proteins. A comprehensive hypothetical mechanism underlying Alzheimer’s disease and other neurodegenerative disorders. Ann N Y Acad Sci 924:62–67

    Article  CAS  PubMed  Google Scholar 

  218. Trojanowski JQ, Mattson MP (2003) Overview of protein aggregation in single, double, and triple neurodegenerative brain amyloidoses. Neuromolecular Med 4:1–6

    CAS  PubMed  Google Scholar 

  219. Tsuboi Y, Ahlskog JE, Apaydin H, Parisi JE, Dickson DW (2001) Lewy bodies are not increased in progressive supranuclear palsy compared with normal controls. Neurology 57:1675–1678

    CAS  PubMed  Google Scholar 

  220. Uchikado H, DelleDonne A, Ahmed Z, Dickson DW (2006) Lewy bodies in progressive supranuclear palsy represent an independent disease process. J Neuropathol Exp Neurol 65:387–395

    CAS  PubMed  Google Scholar 

  221. Uchikado H, DelleDonne A, Uitti R, Dickson DW (2006) Coexistence of PSP and MSA: a case report and review of the literature. Acta Neuropathol 111:186–192

    PubMed  Google Scholar 

  222. Uchikado H, Lin WL, DeLucia MW, Dickson DW (2006) Alzheimer disease with amygdala Lewy bodies: a distinct form of alpha-synucleinopathy. J Neuropathol Exp Neurol 65:685–697

    CAS  PubMed  Google Scholar 

  223. Uryu K, Nakashima-Yasuda H, Forman MS et al (2008) Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67:555–564

    CAS  PubMed  Google Scholar 

  224. Uversky VN, Oldfield CJ, Midic U et al (2009) Unfoldomics of human diseases: linking protein intrinsic disorder with diseases. BMC Genomics 10(Suppl 1):S7

    PubMed  Google Scholar 

  225. Uversky VN, Yamin G, Munishkina LA et al (2005) Effects of nitration on the structure and aggregation of alpha-synuclein. Brain Res Mol Brain Res 134:84–102

    CAS  PubMed  Google Scholar 

  226. Vance C, Rogelj B, Hortobagyi T et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211

    CAS  PubMed  Google Scholar 

  227. Vega IE, Cui L, Propst JA, Hutton ML, Lee G, Yen SH (2005) Increase in tau tyrosine phosphorylation correlates with the formation of tau aggregates. Brain Res Mol Brain Res 138:135–144

    CAS  PubMed  Google Scholar 

  228. Vemuri P, Wiste HJ, Weigand SD et al (2009) MRI and CSF biomarkers in normal, MCI, and AD subjects: predicting future clinical change. Neurology 73:294–301

    CAS  PubMed  Google Scholar 

  229. Wakabayashi K, Hayashi S, Yoshimoto M, Kudo H, Takahashi H (2000) NACP/alpha-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson’s disease brains. Acta Neuropathol 99:14–20

    CAS  PubMed  Google Scholar 

  230. Wakabayashi K, Kawachi I, Toyoshima Y, Takahashi H (1999) Occurrence of argyrophilic grains in multiple system atrophy: histopathological examination of 26 autopsy cases. No To Shinkei 51:433–437

    CAS  PubMed  Google Scholar 

  231. Wakabayashi K, Takahashi H (2006) Cellular pathology in multiple system atrophy. Neuropathology 26:338–345

    PubMed  Google Scholar 

  232. Wakabayashi K, Tanji K, Mori F, Takahashi H (2007) The Lewy body in Parkinson’s disease: molecules implicated in the formation and degradation of alpha-synuclein aggregates. Neuropathology 27:494–506

    PubMed  Google Scholar 

  233. Wang JZ, Grundke-Iqbal I, Iqbal K (1996) Glycosylation of microtubule-associated protein tau: an abnormal posttranslational modification in Alzheimer’s disease. Nat Med 2:871–875

    CAS  PubMed  Google Scholar 

  234. Wang Q, Woltjer RL, Cimino PJ, Pan C, Montine KS, Zhang J, Montine TJ (2005) Proteomic analysis of neurofibrillary tangles in Alzheimer disease identifies GAPDH as a detergent-insoluble paired helical filament tau binding protein. FASEB J 19:869–871

    CAS  PubMed  Google Scholar 

  235. Wang Z, Udeshi ND, O’Malley M, Shabanowitz J, Hunt DF, Hart GW (2009) Enrichment and site-mapping of O-Linked N-Acetylglucosamine by a combination of chemical/enzymatic tagging, photochemical cleavage, and electron transfer dissociation (ETD) mass spectrometry. Mol Cell Proteomics (in press)

  236. Watanabe A, Hong WK, Dohmae N, Takio K, Morishima-Kawashima M, Ihara Y (2004) Molecular aging of tau: disulfide-independent aggregation and non-enzymatic degradation in vitro and in vivo. J Neurochem 90:1302–1311

    CAS  PubMed  Google Scholar 

  237. Watanabe A, Takio K, Ihara Y (1999) Deamidation and isoaspartate formation in smeared tau in paired helical filaments. Unusual properties of the microtubule-binding domain of tau. J Biol Chem 274:7368–7378

    CAS  PubMed  Google Scholar 

  238. Wenning GK, Stefanova N, Jellinger KA, Poewe W, Schlossmacher MG (2008) Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol 64:239–246

    CAS  PubMed  Google Scholar 

  239. Williams DR, Holton JL, Strand C, Pittman A, de Silva R, Lees AJ, Revesz T (2007) Pathological tau burden and distribution distinguishes progressive supranuclear palsy-parkinsonism from Richardson’s syndrome. Brain 130:1566–1576

    PubMed  Google Scholar 

  240. Wiltfang J, Esselmann H, Smirnov A et al (2003) Beta-amyloid peptides in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Ann Neurol 54:263–267

    CAS  PubMed  Google Scholar 

  241. Wirths O, Weickert S, Majtenyi K et al (2000) Lewy body variant of Alzheimer’s disease: alpha-synuclein in dystrophic neurites of A beta plaques. Neuroreport 11:3737–3741

    CAS  PubMed  Google Scholar 

  242. Woulfe J, Gray DA, Mackenzie IR (2009) FUS-immunoreactive intranuclear inclusions in neurodegenerative disease. Brain Pathol. doi:BPA337[pii]10.1111/j.1750-3639.2009.00337.x

  243. Wray S, Saxton M, Anderton BH, Hanger DP (2008) Direct analysis of tau from PSP brain identifies new phosphorylation sites and a major fragment of N-terminally cleaved tau containing four microtubule-binding repeats. J Neurochem 105:2343–2352

    CAS  PubMed  Google Scholar 

  244. Yamazaki M, Arai Y, Baba M et al (2000) Alpha-synuclein inclusions in amygdala in the brains of patients with the parkinsonism-dementia complex of Guam. J Neuropathol Exp Neurol 59:585–591

    CAS  PubMed  Google Scholar 

  245. Yokota O, Bigio EH, Ishizu H et al (2010) Phosphorylated TDP-43 accumulation in the limbic system in progressive supranuclear palsy. 111th meeting of the British Neuropathological Society. Neuropathol Appl Neurobiol 36(Suppl 1):29–30

  246. Yuan J, Xiao X, McGeehan J et al (2006) Insoluble aggregates and protease-resistant conformers of prion protein in uninfected human brains. J Biol Chem 281:34848–34858

    CAS  PubMed  Google Scholar 

  247. Zemaitaitis MO, Lee JM, Troncoso JC, Muma NA (2000) Transglutaminase-induced cross-linking of tau proteins in progressive supranuclear palsy. J Neuropathol Exp Neurol 59:983–989

    CAS  PubMed  Google Scholar 

  248. Zetterberg H, Ruetschi U, Portelius E et al (2008) Clinical proteomics in neurodegenerative disorders. Acta Neurol Scand 118:1–11

    CAS  PubMed  Google Scholar 

  249. Zou WQ, Gambetti P (2007) Prion: the chameleon protein. Cell Mol Life Sci 64:3266–3270

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by EU FP6 Projects, BNEII No LSHM-CT-2004-503039 and Neuroscreen LSHB-CZ-2006-037719 contract No. 037719.

Author information

Authors and Affiliations

  1. Institute of Neurology, Medical University of Vienna, AKH 4J, Währinger Gürtel 18-20, 1097, Vienna, Austria

    Gabor G. Kovacs, Gergő Botond & Herbert Budka

Authors
  1. Gabor G. Kovacs
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gergő Botond
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Herbert Budka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gabor G. Kovacs.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kovacs, G.G., Botond, G. & Budka, H. Protein coding of neurodegenerative dementias: the neuropathological basis of biomarker diagnostics. Acta Neuropathol 119, 389–408 (2010). https://doi.org/10.1007/s00401-010-0658-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-010-0658-1

Keywords

Search

Navigation