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Cited by 831Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Caspase cleavage of tau: Linking amyloid and neurofibrillary tangles in Alzheimer's disease

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Gamblin, T. Chris, Chen, Feng, Zambrano, Angara, Abraha, Aida, Lagalwar, Sarita, Guillozet, Angela L., Lu, Meiling, Fu, Yifan +6 more·2003·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1630428100PMC PMC187753
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Abstract

The principal pathological features of Alzheimer's disease (AD) are extracellular amyloid plaques and intracellular neurofibrillary tangles, the latter composed of the microtubule-binding protein tau assembled into paired helical and straight filaments. Recent studies suggest that these pathological entities may be functionally linked, although the mechanisms by which amyloid deposition promotes pathological tau filament assembly are poorly understood. Here, we report that tau is proteolyzed by multiple caspases at a highly conserved aspartate residue (Asp 421 ) in its C terminus in vitro and in neurons treated with amyloid-β (Aβ) (1–42) peptide. Tau is rapidly cleaved at Asp 421 in Aβ-treated neurons (within 2 h), and its proteolysis appears to precede the nuclear events of apoptosis. We also demonstrate that caspase cleavage of tau generates a truncated protein that lacks its C-terminal 20 amino acids and assembles more rapidly and more extensively into tau filaments in vitro than wild-type tau. Using a monoclonal antibody that specifically recognizes tau truncated at Asp 421 , we show that tau is proteolytically cleaved at this site in the fibrillar pathologies of AD brain. Taken together, our results suggest a novel mechanism linking amyloid deposition and neurofibrillary tangles in AD: Aβ peptides promote pathological tau filament assembly in neurons by triggering caspase cleavage of tau and generating a proteolytic product with enhanced polymerization kinetics.

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  1. [1]Yuan, J. & Yankner, B. A. (2000) Nature 407, 802–809. [DOI] [PubMed] [Google Scholar]
  2. Rao, D. & Lee, V. M. (1993) Brain Pathol. 3, 45–54. [DOI] [PubMed] [Google Scholar]
  3. [3]Hardy, J. & Selkoe, D. J. (2002) Science 297, 353–356. [DOI] [PubMed] [Google Scholar]
  4. [4]Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., Houlden, H., Pickering-Brown, S., Chakraverty, S., Isaacs, A., Grover, A., et al. (1998) Nature 393, 702–705. [DOI] [PubMed] [Google Scholar]
  5. Klug, A. & Ghetti, B. (1998) Proc. Natl. Acad. Sci. USA 95, 7737–7741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. [6]Clark, L. N., Poorkaj, P., Wszolek, Z., Geschwind, D. H., Nasreddine, Z. S., Miller, B., Li, D., Payami, H., Awert, F., Markopoulou, K., et al. (1998) Proc. Natl. Acad. Sci. USA 95, 13103–13107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. [7]Gotz, J., Chen, F., van Dorpe, J. & Nitsch, R. M. (2001) Science 293, 1491–1495. [DOI] [PubMed] [Google Scholar]
  8. [8]Lewis, J., Dickson, D. W., Lin, W. L., Chisholm, L., Corral, A., Jones, G., Yen, S. H., Sahara, N., Skipper, L., Yager, D., et al. (2001) Science 293, 1487–1491. [DOI] [PubMed] [Google Scholar]
  9. H. M. & Binder, L. I. (1986) Proc. Natl. Acad. Sci. USA 83, 4913–4917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. [10]Novak, M., Kabat, J. & Wischik, C. M. (1993) EMBO J. 12, 365–370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. [11]Alonso, A. C., Zaidi, T., Grundke-Iqbal, I. & Iqbal, K. (1994) Proc. Natl. Acad. Sci. USA 91, 5562–5566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kuret, J. & Binder, L. I. (2000) J. Cell Sci. 113, 3737–3745. [DOI] [PubMed] [Google Scholar]
  13. [13]Alonso, A., Zaidi, T., Novak, M., Grundke-Iqbal, I. & Iqbal, K. (2001) Proc. Natl. Acad. Sci. USA 98, 6923–6928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. [14]Gervais, F. G., Xu, D., Robertson, G. S., Vaillancourt, J. P., Zhu, Y., Huang, J., LeBlanc, A., Smith, D., Rigby, M., Shearman, M. S., et al. (1999) Cell 97, 395–406. [DOI] [PubMed] [Google Scholar]
  15. A. & Yuan, J. (2000) Nature 403, 98–103. [DOI] [PubMed] [Google Scholar]
  16. Brown, K. & Shelanski, M. L. (2000) J. Neurosci. 20, 1386–1392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. [17]Canu, N., Dus, L., Barbato, C., Ciotti, M. T., Brancolini, C., Rinaldi, A. M., Novak, M., Cattaneo, A., Bradbury, A. & Calissano, P. (1998) J. Neurosci. 18, 7061–7074. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. C., Verzillo, V., Novak, M. & Cattaneo, A. (2000) J. Neurochem. 75, 624–633. [DOI] [PubMed] [Google Scholar]
  19. [19]Chung, C. W., Song, Y. H., Kim, I. K., Yoon, W. J., Ryu, B. R., Jo, D. G., Woo, H. N., Kwon, Y. K., Kim, H. H., Gwag, B. J., et al. (2001) Neurobiol. Dis. 8, 162–172. [DOI] [PubMed] [Google Scholar]
  20. Ghanem, L., Parker, P. J., Kirschner, M. W. & Yuan, J. (1997) J. Biol. Chem. 272, 29449–29453. [DOI] [PubMed] [Google Scholar]
  21. [21]Cryns, V. L., Bergeron, L., Zhu, H., Li, H. & Yuan, J. (1996) J. Biol. Chem. 271, 31277–31282. [DOI] [PubMed] [Google Scholar]
  22. [22]Binder, L. I., Frankfurter, A. & Rebhun, L. I. (1985) J. Cell Biol. 101, 1371–1378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. [23]Carmel, G., Mager, E. M., Binder, L. I. & Kuret, J. (1996) J. Biol. Chem. 271, 32789–32795. [DOI] [PubMed] [Google Scholar]
  24. [24]Alvarez, A., Toro, R., Cáceres, A. & Maccioni, R. B. (1999) FEBS Lett. 459, 421–426. [DOI] [PubMed] [Google Scholar]
  25. [25]Alvarez, A., Muñoz, J. P. & Maccioni, R. B. (2001) Exp. Cell Res. 64, 266–274. [DOI] [PubMed] [Google Scholar]
  26. [26]LoPresti, P., Szuchet, S., Papasozomenos, S. C., Zinkowski, R. P. & Binder, L. I. (1995) Proc. Natl. Acad. Sci. USA 92, 10369–10373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. [27]Thurston, V. C., Pena, P., Pestell, R. & Binder, L. I. (1997) Cell Motil. Cytoskeleton 38, 100–110. [DOI] [PubMed] [Google Scholar]
  28. J., Kuret, J., Berry, R. W. & Binder, L. I. (2001) J. Neurochem. 77, 1372–1385. [DOI] [PubMed] [Google Scholar]
  29. [29]Kamradt, M. C., Chen F., Sam S. & Cryns, V. L. (2002) J. Biol. Chem. 277, 38731–38736. [DOI] [PubMed] [Google Scholar]
  30. Berry, R. W. & Binder, L. I. (2000) Biochemistry 39, 6136–6144. [DOI] [PubMed] [Google Scholar]
  31. [31]Lazebnik, Y. A., Kaufmann, S. H., Desnoyers, S., Poirier, G. G. & Earnshaw, W. C. (1994) Nature 371, 346–347. [DOI] [PubMed] [Google Scholar]
  32. [32]Slee, E. A., Adrain, C. & Martin, S. J. (2001) J. Biol. Chem. 276, 7320–7326. [DOI] [PubMed] [Google Scholar]
  33. [33]Mena, R., Edwards, P. C., Perez-Olvera, O. & Wischik, C. M. (1995) Acta Neuropathol. 89, 50–56. [DOI] [PubMed] [Google Scholar]
  34. [34]Dammerman, M., Yen, S. H. & Shafit-Zagardo, B. (1989) J. Neurosci. Res. 24, 487–495. [DOI] [PubMed] [Google Scholar]
  35. Ferreira, A. (2002) Proc. Natl. Acad. Sci. USA 99, 6364–6369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. [36]Goode, B. L. & Feinstein, S. C. (1994) J. Cell Biol. 124, 769–782. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. [37]Goode, B. L., Chau, M., Denis, P. E. & Feinstein, S. C. (2000) J. Biol. Chem. 275, 38182–38189. [DOI] [PubMed] [Google Scholar]
  38. [38]Ackmann, M., Wiech, H. & Mandelkow, E. (2000) J. Biol. Chem. 275, 30335–30343. [DOI] [PubMed] [Google Scholar]
  39. Dikkes, P. & Tsai, L. H. (1999) Nature 402, 615–622. [DOI] [PubMed] [Google Scholar]
  40. [40]Harrington, C. R., Mukaetova-Ladinska, E. B., Hills, R., Edwards, P. C., Montejo de Garcini, E., Novak, M. & Wischik, C. M. (1991) Proc. Natl. Acad. Sci. USA 88, 5842–5846. [DOI] [PMC free article] [PubMed] [Google Scholar]

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Authors
Gamblin, T. C., Chen, F., Zambrano, A., Abraha, A., Lagalwar, S., Guillozet, A. L., Lu, M., Fu, Y., Garcia-Sierra, F., LaPointe, N., Miller, R., Berry, R. W., Binder, L. I., & Cryns, V. L.
Affiliations
  • Northwestern University (US)
  • Departments of Cell and Molecular Biology and Biochemistry and Molecular Pharmacology; Cell Death Regulation Laboratory, Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine; and Cognitive Neurology and Alzheimer's Disease Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2003-07-29
Volume
100
Issue
17
Pages
10032-10037
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1630428100
PMC
PMC187753
OpenAlex
W2125172225
Cited by
831
References
43
Citations by year
2026: 20 · 2025: 27 · 2024: 27 · 2023: 30 · 2022: 30 · 2021: 40 · 2020: 43 · 2019: 35 · 2018: 36 · 2017: 36 · 2016: 47 · 2015: 40 · 2014: 34 · 2013: 36 · 2012: 37
FWCI
16.67
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute on Aging (AG09466, P01AG009466)
  • National Institute of Neurological Disorders and Stroke (NS31957, R01NS031957)
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, caspase cleavage, Alzheimer's disease, amyloid-beta, neurofibrillary tangles, amyloid plaques, apoptosis, tau truncation, paired helical filaments
MeSH terms
Alzheimer Disease, Amyloid, Animals, Antibodies, Monoclonal, Aspartic Acid, Base Sequence, Binding Sites, Humans, Neurons, Recombinant Proteins, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Apoptosis, Sequence Deletion, DNA, Complementary, Caspases, Mice, In Vitro Techniques

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