CoChat
Sign Up
Cited by 54Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Tau Aggregation and Toxicity in Tauopathic Neurodegenerative Diseases

Open access
Honson, Nicolette S., Kuret, Jeff·2008·Journal of Alzheimer's Disease
DOI 10.3233/jad-2008-14409PMC PMC2748882
Open this paper in CoChat — free account

Abstract

Since its discovery as a structural component of neurofibrillary lesions of Alzheimer's disease more than twenty years ago, tau protein has been implicated in the cascade of events associated with neurodegeneration. Specifically, the "tau hypothesis" posits that misfunction of tau, which occurs in response to unknown stimuli, results in its intracellular assembly into filaments that eventually prove toxic to the cells that produce them. The tau hypothesis is supported by numerous neuropathological and genetic observations of authentic human disease cases. However, experiments designed to study aggregate toxicity in biological models suggest that some aggregate species may be inert or could potentially serve a neuroprotective function. Distinguishing these possibilities experimentally has been complicated by currently available biological models, which do not fully recapitulate aggregation conditions seen in disease. Additional model systems which better approximate physiological conditions may help elucidate the molecular mechanisms involved in aggregation associated toxicity. Here we examine the accumulated evidence linking aggregation and neurodegeneration, and experimental approaches to the problem of tau aggregation-mediated toxicity.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3233/jad-2008-14409

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The tau hypothesis emphasizes hyperphosphorylated tau forming neurofibrillary tangles and disrupting cytoskeletal integrity.

    “The tau hypothesis emphasizes the role of hyperphosphorylated tau in forming neurofibrillary tangles and disrupting cytoskeletal integrity [9, 10].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [10]

    Sections 1 and 2 link tau phosphorylation to reduced microtubule binding and describe tau aggregation in neurofibrillary tangles. But Section 4 says tau sequestration has only minor effects on microtubule function when other proteins compensate, and that loss of tau function alone cannot directly cause cytoskeletal collapse. The claim overstates the paper's support for disruption of cytoskeletal integrity. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 56

  1. [1]Alonso AD Grundke-Iqbal I Barra HS Iqbal K Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau Proc. Natl. Acad. Sci. U.S.A 1997 94 298 303 8990203 PMC19321
  2. [2]Amadoro G Ciotti MT Costanzi M Cestari V Calissano P Canu N NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation Proc. Natl. Acad. Sci. U.S.A 2006 103 2892 2897 16477009 PMC1413822
  3. [4]Bandyopadhyay B Li G Yin H Kuret J Tau aggregation and toxicity in a cell culture model of tauopathy J. Biol. Chem 2007 282 16454 16464 17428800
  4. [5]Berger Z Roder H Hanna A Carlson A Rangachari V Yue M Wszolek Z Ashe K Knight J Dickson D Andorfer C Rosenberry TL Lewis J Hutton M Janus C Accumulation of pathological tau species and memory loss in a conditional model of tauopathy J. Neurosci 2007 27 3650 3662 17409229 PMC6672413
  5. [6]Berriman J Serpell LC Oberg KA Fink AL Goedert M Crowther RA Tau filaments from human brain and from in vitro assembly of recombinant protein show cross-β structure Proc. Natl. Acad. Sci. U. S. A 2003 100 9034 9038 12853572 PMC166433
  6. [7]Biernat J Gustke N Drewes G Mandelkow EM Mandelkow E Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: distinction between PHF-like immunoreactivity and microtubule binding Neuron 1993 11 153 163 8393323
  7. [9]Bramblett GT Goedert M Jakes R Merrick SE Trojanowski JQ Lee VM Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding Neuron 1993 10 1089 1099 8318230
  8. [10]Brion JP Tremp G Octave JN Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer's disease Am. J. Pathol 1999 154 255 270 9916940 PMC1853433
  9. [11]Cash AD Aliev G Siedlak SL Nunomura A Fujioka H Zhu X Raina AK Vinters HV Tabaton M Johnson AB Paula-Barbosa M Avila J Jones PK Castellani RJ Smith MA Perry G Microtubule reduction in Alzheimer's disease and aging is independent of tau filament formation Am. J. Pathol 2003 162 1623 1627 12707046 PMC1851211
  10. [12]Caughey B Lansbury PT Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders Annu. Rev. Neurosci 2003 26 267 298 12704221
  11. [13]Chang E Kuret J Detection and quantification of tau aggregation using a membrane filter assay Anal. Biochem 2008 in press PMC2359897 17949677
  12. [14]Chimon S Shaibat MA Jones CR Calero DC Aizezi B Ishii Y Evidence of fibril-like β-sheet structures in a neurotoxic amyloid intermediate of Alzheimer's β-amyloid Nat. Struct. Mol. Biol 2007 14 1157 1164 18059284
  13. [15]Chirita CN Congdon EE Yin H Kuret J Triggers of full-length tau aggregation: a role for partially folded intermediates Biochemistry 2005 44 5862 5872 15823045
  14. [16]Congdon EE Kim S Bonchak J Songrug T Matzavinos A Kuret J Nucleation dependent tau filament formation: the importance of dimerization and an estimation of elementary rate constants J. Biol. Chem 2008 283 in press PMC2376241 18359772
  15. [18]Cripps D Thomas SN Jeng Y Yang F Davies P Yang AJ Alzheimer disease-specific conformation of hyperphosphorylated paired helical filament-Tau is polyubiquitinated through Lys-48, Lys-11, and Lys-6 ubiquitin conjugation J. Biol. Chem 2006 281 10825 10838 16443603
  16. [19]Drubin DG Feinstein SC Shooter EM Kirschner MW Nerve growth factor-induced neurite outgrowth in PC12 cells involves the coordinate induction of microtubule assembly and assembly-promoting factors J. Cell Biol 1985 101 1799 1807 2997236 PMC2113947
  17. [20]Eckermann K Mocanu MM Khlistunova I Biernat J Nissen A Hofmann A Schonig K Bujard H Haemisch A Mandelkow E Zhou L Rune G Mandelkow EM The β-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of tauopathy J. Biol. Chem 2007 282 31755 31765 17716969
  18. [21]Friedhoff P Schneider A Mandelkow EM Mandelkow E Rapid assembly of Alzheimer-like paired helical filaments from microtubule-associated protein tau monitored by fluorescence in solution Biochemistry 1998 37 10223 10230 9665729
  19. [22]Gamblin TC King ME Dawson H Vitek MP Kuret J Berry RW Binder LI In vitro polymerization of tau protein monitored by laser light scattering: method and application to the study of FTDP-17 mutants Biochemistry 2000 39 6136 6144 10821687
  20. [23]Ghoshal N Garcia-Sierra F Wuu J Leurgans S Bennett DA Berry RW Binder LI Tau conformational changes correspond to impairments of episodic memory in mild cognitive impairment and Alzheimer's disease Exp. Neurol 2002 177 475 493 12429193
  21. [24]Goedert M Spillantini MG Jakes R Rutherford D Crowther RA Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease Neuron 1989 3 519 526 2484340
  22. [26]Goode BL Chau M Denis PE Feinstein SC Structural and functional differences between 3-repeat and 4-repeat tau isoforms. Implications for normal tau function and the onset of neurodegenerative disease J. Biol. Chem 2000 275 38182 38189 10984497
  23. [27]Gotz J Probst A Spillantini MG Schafer T Jakes R Burki K Goedert M Somatodendritic localization and hyperphosphorylation of tau protein in transgenic mice expressing the longest human brain tau isoform EMBO J 1995 14 1304 1313 7729409 PMC398215
  24. [28]Gotz J Deters N Doldissen A Bokhari L Ke Y Wiesner A Schonrock N Ittner LM A decade of tau transgenic animal models and beyond Brain Pathol 2007 17 91 103 17493043 PMC8095624
  25. [29]Gross PG Kartalov EP Scherer A Weiner LP Applications of microfluidics for neuronal studies J. Neurol. Sci 2007 252 135 143 17207502
  26. [30]Harada A Oguchi K Okabe S Kuno J Terada S Ohshima T Sato-Yoshitake R Takei Y Noda T Hirokawa N Altered microtubule organization in small-calibre axons of mice lacking tau protein Nature 1994 369 488 491 8202139
  27. [31]Holzer M Craxton M Jakes R Arendt T Goedert M Tau gene (MAPT) sequence variation among primates Gene 2004 341 313 322 15474313
  28. [32]Kenessey A Yen SH The extent of phosphorylation of fetal tau is comparable to that of PHF-tau from Alzheimer paired helical filaments Brain Res 1993 629 40 46 8287279
  29. [33]Khatoon S Grundke-Iqbal I Iqbal K Brain levels of microtubule-associated protein tau are elevated in Alzheimer's disease: a radioimmuno-slot-blot assay for nanograms of the protein J. Neurochem 1992 59 750 753 1629745
  30. [34]Khatoon S Grundke-Iqbal I Iqbal K Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains FEBS Lett 1994 351 80 84 8076698
  31. [35]Kimura T Ono T Takamatsu J Yamamoto H Ikegami K Kondo A Hasegawa M Ihara Y Miyamoto E Miyakawa T Sequential changes of tau-site-specific phosphorylation during development of paired helical filaments Dementia 1996 7 177 181 8835879
  32. [36]King ME Ahuja V Binder LI Kuret J Ligand-dependent tau filament formation: implications for Alzheimer's disease progression Biochemistry 1999 38 14851 14859 10555967
  33. [37]King ME Gamblin TC Kuret J Binder LI Differential assembly of human tau isoforms in the presence of arachidonic acid J. Neurochem 2000 74 1749 1757 10737634
  34. [38]Kopke E Tung YC Shaikh S Alonso AC Iqbal K Grundke-Iqbal I Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease J. Biol. Chem 1993 268 24374 24384 8226987
  35. [39]Ksiezak-Reding H Binder LI Yen SH Immunochemical and biochemical characterization of τ proteins in normal and Alzheimer's disease brains with Alz 50 and Tau-1 J. Biol. Chem 1988 263 7948 7953 3131334
  36. [40]Ksiezak-Reding H Liu WK Yen SH Phosphate analysis and dephosphorylation of modified tau associated with paired helical filaments Brain Res 1992 597 209 219 1472994
  37. [41]Ksiezak-Reding H Wall JS Characterization of paired helical filaments by scanning transmission electron microscopy Microsc. Res. Tech 2005 67 126 140 16104001
  38. [43]Maeda S Sahara N Saito Y Murayama M Yoshiike Y Kim H Miyasaka T Murayama S Ikai A Takashima A Granular tau oligomers as intermediates of tau filaments Biochemistry 2007 46 3856 3861 17338548
  39. [44]Mitchell TW Nissanov J Han LY Mufson EJ Schneider JA Cochran EJ Bennett DA Lee VM Trojanowski JQ Arnold SE Novel method to quantify neuropil threads in brains from elders with or without cognitive impairment J. Histochem. Cytochem 2000 48 1627 1638 11101631
  40. [45]Mocanu MM Nissen A Eckermann K Khlistunova I Biernat J Drexler D Petrova O Schonig K Bujard H Mandelkow E Zhou L Rune G Mandelkow EM The potential for β-structure in the repeat domain of tau protein determines aggregation, synaptic decay, neuronal loss, and coassembly with endogenous Tau in inducible mouse models of tauopathy J. Neurosci 2008 28 737 748 18199773 PMC6670355
  41. [47]Nagai Y Inui T Popiel HA Fujikake N Hasegawa K Urade Y Goto Y Naiki H Toda T A toxic monomeric conformer of the polyglutamine protein Nat. Struct. Mol. Biol 2007 14 332 340 17369839
  42. [48]Park SY Ferreira A The generation of a 17 kDa neurotoxic fragment: an alternative mechanism by which tau mediates β-amyloid-induced neurodegeneration J. Neurosci 2005 25 5365 5375 15930385 PMC1352316
  43. [49]Pickering-Brown SM Baker M Gass J Boeve BF Loy CT Brooks WS Mackenzie IR Martins RN Kwok JB Halliday GM Kril J Schofield PR Mann DM Hutton M Mutations in progranulin explain atypical phenotypes with variants in MAPT Brain 2006 129 3124 3126 17071927
  44. [50]Royall DR Palmer R Mulroy AR Polk MJ Roman GC David JP Delacourte A Pathological determinants of the transition to clinical dementia in Alzheimer's disease Exp. Aging Res 2002 28 143 162 11928525
  45. [51]Santacruz K Lewis J Spires T Paulson J Kotilinek L Ingelsson M Guimaraes A DeTure M Ramsden M McGowan E Forster C Yue M Orne J Janus C Mariash A Kuskowski M Hyman B Hutton M Ashe KH Tau suppression in a neurodegenerative mouse model improves memory function Science 2005 309 476 481 16020737 PMC1574647
  46. [52]Sassin I Schultz C Thal DR Rub U Arai K Braak E Braak H Evolution of Alzheimer's disease-related cytoskeletal changes in the basal nucleus of Meynert Acta Neuropathol. (Berl) 2000 100 259 269 10965795
  47. [53]Sawaya MR Sambashivan S Nelson R Ivanova MI Sievers SA Apostol MI Thompson MJ Balbirnie M Wiltzius JJ McFarlane HT Madsen AO Riekel C Eisenberg D Atomic structures of amyloid cross-β spines reveal varied steric zippers Nature 2007 447 453 457 17468747
  48. [54]Schonheit B Zarski R Ohm TG Spatial and temporal relationships between plaques and tangles in Alzheimer-pathology Neurobiol. Aging 2004 25 697 711 15165691
  49. [55]Seubert P Mawal-Dewan M Barbour R Jakes R Goedert M Johnson GV Litersky JM Schenk D Lieberburg I Trojanowski JQ Lee VM Detection of phosphorylated Ser262 in fetal tau, adult tau, and paired helical filament tau J. Biol. Chem 1995 270 18917 18922 7642549
  50. [56]Sharma VM Litersky JM Bhaskar K Lee G Tau impacts on growth-factor-stimulated actin remodeling J. Cell Sci 2007 120 748 757 17284520
  51. [57]Stefani M Dobson CM Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution J. Mol. Med 2003 81 678 699 12942175
  52. [58]Terwel D Lasrado R Snauwaert J Vandeweert E Van Haesendonck C Borghgraef P Van Leuven F Changed conformation of mutant Tau-P301L underlies the moribund tauopathy, absent in progressive, nonlethal axonopathy of Tau-4R/2N transgenic mice J. Biol. Chem 2005 280 3963 3973 15509565
  53. [59]van Swieten J Spillantini MG Hereditary frontotemporal dementia caused by Tau gene mutations Brain Pathol 2007 17 63 73 17493040 PMC8095608
  54. [60]von Bergen M Barghorn S Muller SA Pickhardt M Biernat J Mandelkow EM Davies P Aebi U Mandelkow E The core of tau-paired helical filaments studied by scanning transmission electron microscopy and limited proteolysis Biochemistry 2006 45 6446 6457 16700555
  55. [61]Wittmann CW Wszolek MF Shulman JM Salvaterra PM Lewis J Hutton M Feany MB Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles Science 2001 293 711 714 11408621
  56. [62]Yuan A Kumar A Peterhoff C Duff K Nixon RA Axonal transport rates in vivo are unaffected by tau deletion or overexpression in mice J. Neurosci 2008 28 1682 1687 18272688 PMC2814454

Cited by

Sorted by citations

Authors
Honson, N. S., & Kuret, J.
Affiliations
The Ohio State University (US)
Corresponding author
Kuret, Jeff
ORCID
Kuret, Jeff
Venue
Journal of Alzheimer's Disease
Publisher
SAGE Publications
Published
2008-07-24
Volume
14
Issue
4
Pages
417-422
ISSN
  • 1387-2877 (ISSN-L)
  • 1875-8908
DOI
10.3233/jad-2008-14409
PMC
PMC2748882
OpenAlex
W1660425957
Cited by
54
References
6
Citations by year
2026: 6 · 2025: 5 · 2023: 3 · 2022: 2 · 2021: 3 · 2020: 6 · 2018: 1 · 2017: 3 · 2015: 1 · 2014: 5 · 2013: 3 · 2012: 4
FWCI
2.56
Type
journal article
Language
en
Open access
Locations
  • Journal of Alzheimer s Disease (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute on Aging (R01AG014452, AG 14452)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
tau protein, tau aggregation
MeSH terms
Animals, Humans, tau Proteins, Neurodegenerative Diseases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review