The Generation of a 17 kDa Neurotoxic Fragment: An Alternative Mechanism by which Tau Mediates β-Amyloid-Induced Neurodegeneration
Open accessAbstract
Recently, we have shown that the microtubule-associated protein tau is essential for β-amyloid (Aβ)-induced neurotoxicity in hippocampal neurons. However, the mechanisms by which tau mediates Aβ-induced neurite degeneration remain poorly understood. In the present study, we analyzed whether tau cleavage played a role in these events. Our results showed that pre-aggregated Aβ induced the generation of a 17 kDa tau fragment in cultured hippocampal neurons. The generation of this fragment was preceded by the activation of calpain-1. Conversely, inhibitors of this protease, but not of caspases, completely prevented tau proteolysis leading to the generation of the 17 kDa fragment and significantly reduced Aβ-induced neuronal death. Furthermore, the expression of this fragment in cultured hippocampal neurons induced the formation of numerous varicosity-bearing tortuous processes, as well as the complete degeneration of some of those neurite processes. These results suggest that Aβ-induced neurotoxicity may be mediated, at least in part, through the calpain-mediated generation of a toxic 17 kDa tau fragment. Collectively, these results provide insight into a novel mechanism by which tau could mediate Aβ-induced neurotoxicity.
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.
Integrity signals
Registry
Cites
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.
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?
Once tau is eliminated, glia appear better able to mount context and disease-appropriate responses, including elimination of toxic species, reduction in kinase activation, and modulation of downstream signaling, potentially explaining the broad protective effects of tau ablation across pathological models.
“Once tau is eliminated, glia appear better able to mount context and disease-appropriate responses, including elimination of toxic species [144], reduction in kinase activation, and modulation of downstream signaling [76, 78, 145], potentially explaining the broad protective effects of tau ablation across pathological models.”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [144]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredCalpain A has been shown to cleave tau and is reported to be responsible for producing a 17 kDa fragment that may be a highly toxic tau derivative.
“Indeed, calpain A has been shown to cleave tau and is reported to be responsible for producing a 17 kDa fragment that may be a highly toxic tau derivative (211,212).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [211]
Calpain-2 cleaves tau at Arg230.
“while calpain-2 cleaves tau at Arg230 [202–206].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [204]
Calpain-mediated tau cleavage generates several truncated tau isoforms, including 17 kDa tau45-230, and 24 kDa tau243-441 products.
“Calpain-mediated tau cleavage generates several truncated tau isoforms, including 17 kDa tau45–230, and 24 kDa tau243–441 products [204, 207].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [204]
Calpain-1 cleaves tau at Lys44, Arg230, Arg242, Gly323, and Gly326.
“Calpain-1 cleaves tau at Lys44, Arg230, Arg242, Gly323, and Gly326”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [204]
Tau45-230 is neurotoxic, and can induce synaptic and cognitive impairment.
“a recent study utilizing tau45–230 transgenic mice indicates that tau45–230 is neurotoxic, and can induce synaptic and cognitive impairment [204, 205, 209].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [204]
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
PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT
Lowry, O. H., Rosebrough, N., Farr, A. L., & Randall, R. (1951) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)52451-6 · Cited by 315,771 · see citing works
Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4
LAEMMLI, U. K. (1970) · Nature · doi:10.1038/227680a0 · Cited by 249,961 · see citing works
Towbin, H., Staehelin, T., & Gordon, J. (1979) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.76.9.4350 · Cited by 51,421 · see citing works
Raza, H., John, A., & Nemmar, A. (2013) · Cellular Physiology and Biochemistry · doi:10.1159/000350087 · Cited by 47,311 · see citing works
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359 · see citing works
Glenner, G. G., & Wong, C. W. (1984) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(84)80190-4 · Cited by 5,404 · see citing works
Assay of proteins in the presence of interfering materials
Bensadoun, A., & Weinstein, D. (1976) · Analytical Biochemistry · doi:10.1016/s0003-2697(76)80064-4 · Cited by 3,191 · see citing works
Growth of a rat neuroblastoma cell line in serum-free supplemented medium.
Bottenstein, J. E., & SATO, G. H. (1979) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.76.1.514 · Cited by 2,282 · see citing works
Kosik, K. S., Joachim, C. L., & Selkoe, D. J. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.11.4044 · Cited by 1,462 · see citing works
Neurotoxicity induces cleavage of p35 to p25 by calpain
Lee, M.-S., Kwon, Y. T., Li, M., Peng, J., Friedlander, R. M., & Tsai, L. (2000) · Nature · doi:10.1038/35012636 · Cited by 1,057 · see citing works
Caspase cleavage of tau: Linking amyloid and neurofibrillary tangles in Alzheimer's disease
Gamblin, T. C., Chen, F., Zambrano, A., Abraha, A., Lagalwar, S., Guillozet, A. L., Lu, M., Fu, Y., Garcia-Sierra, F., LaPointe, N., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1630428100 · Cited by 831 · see citing works
Tau is essential to β-amyloid-induced neurotoxicity
Rapoport, M., Dawson, H. N., Binder, L. I., Vitek, M. P., & Ferreira, A. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.092136199 · Cited by 807 · see citing works
Self-citationWood, J. G., Mirra, S. S., Pollock, N. J., & Binder, L. I. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.11.4040 · Cited by 749 · see citing works
Cell Biology of the Amyloid beta-Protein Precursor and the Mechanism of Alzheimer's Disease
Selkoe, D. J. (1994) · Annual Review of Cell Biology · doi:10.1146/annurev.cb.10.110194.002105 · Cited by 748 · see citing works
β-Amyloid fibrils induce tau phosphorylation and loss of microtubule binding
Busciglio, J., Lorenzo, A., Yeh, J., & Yankner, B. A. (1995) · Neuron · doi:10.1016/0896-6273(95)90232-5 · Cited by 595 · see citing works
Saito, K., Elce, J. S., Hamos, J. E., & Nixon, R. A. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.7.2628 · Cited by 579 · see citing works
Gong, C.-X., Lidsky, T., Wegiel, J., Zuck, L., Grundke-Iqbal, I., & Iqbal, K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.8.5535 · Cited by 405 · see citing works
Novak, M., Kabat, J., & Wischik, C. M. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb05665.x · Cited by 398 · see citing works
LoPresti, P., Szuchet, S., Papasozomenos, S. C., Zinkowski, R. P., & Binder, L. I. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.22.10369 · Cited by 388 · see citing works
Tau protein kinase I is essential for amyloid beta-protein-induced neurotoxicity.
Takashima, A., Noguchi, K., Sato, K., Hoshino, T., & Imahori, K. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.16.7789 · Cited by 381 · see citing works
Mattson, M. P., Tomaselli, K. J., & Rydel, R. E. (1993) · Brain Research · doi:10.1016/0006-8993(93)90295-x · Cited by 379 · see citing works
The car☐yl third of tau is tightly bound to paired helical filaments
Kondo, J., Honda, T., Mori, H., Hamada, Y., Miura, R., OGAWARA, M., & Ihara, Y. (1988) · Neuron · doi:10.1016/0896-6273(88)90130-4 · Cited by 355 · see citing works
Caspase-2 Mediates Neuronal Cell Death Induced by β-Amyloid
Troy, C. M., Rabacchi, S. A., Friedman, W., Frappier, T. F., Brown, K. R., & Shelanski, M. L. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-04-01386.2000 · Cited by 354 · see citing works
Intracellular Calcium-Dependent Proteolysis
Mellgren, R. L. (2019) · CRC Press eBooks · doi:10.1201/9781351073813 · Cited by 286 · see citing works
Caspase-Mediated Fragmentation of Calpain Inhibitor Protein Calpastatin during Apoptosis
Wang, K., Posmantur, R. M., Nadimpalli, R., Nath, R., Mohan, P. S., Nixon, R. A., Talanian, R. V., Keegan, M. G., Herzog, L., & Allen, H. (1998) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1998.0748 · Cited by 270 · see citing works
β-Amyloid protein-induced Alzheimer's disease animal model
Nitta, A., Itoh, A., Hasegawa, T., & Nabeshima, T. (1994) · Neuroscience Letters · doi:10.1016/0304-3940(94)90239-9 · Cited by 266 · see citing works
Su, J. H., Zhao, M., Anderson, A. J., Srinivasan, A. N., & Cotman, C. W. (2001) · Brain Research · doi:10.1016/s0006-8993(01)02018-2 · Cited by 260 · see citing works
Estus, S., Tucker, H. M., van Rooyen, C., Wright, S., Brigham, E. F., Wogulis, M. D., & Rydel, R. E. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-20-07736.1997 · Cited by 255 · see citing works
Brancolini, C., Lazarević, D., Rodriguez, J., & Schneider, C. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.139.3.759 · Cited by 236 · see citing works
Tau Cleavage and Dephosphorylation in Cerebellar Granule Neurons Undergoing Apoptosis
Canu, N., Dus, L., Barbato, C., Ciotti, M. T., Brancolini, C., Rinaldi, A. M., Novak, M., Cattaneo, A., Bradbury, A., & Calissano, P. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-18-07061.1998 · Cited by 232 · see citing works
Inhibition of tau phosphorylating protein kinase cdk5 prevents β‐amyloid‐induced neuronal death
Alvarez, A. R., Toro, R., Cáceres, A., & Maccioni, R. B. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01279-x · Cited by 228 · see citing works
Toxicity of Amyloid β Peptide: Tales of Calcium, Mitochondria, and Oxidative Stress
Canevari, L., Abramov, A. Y., & Duchen, M. R. (2004) · Neurochemical Research · doi:10.1023/b:nere.0000014834.06405.af · Cited by 221 · see citing works
Proapoptotic Effects of Tau Cleavage Product Generated by Caspase-3
Chung, C.-W., Song, Y.-H., Kim, I.-K., Yoon, W. J., Ryu, B. R., Jo, D., Woo, H., Kwon, Y.-K., Kim, H., Gwag, B.-J., et al. (2001) · Neurobiology of Disease · doi:10.1006/nbdi.2000.0335 · Cited by 211 · see citing works
β-Amyloid and the Pathogenesis of Alzheimer's Disease
Flier, J. S., Underhill, L. H., Yankner, B. A., & Mesulam, M. M. (1991) · New England Journal of Medicine · doi:10.1056/nejm199112263252605 · Cited by 207 · see citing works
Szendrei, G., Lee, V. M. Y., & Otvos, L. (1993) · Journal of Neuroscience Research · doi:10.1002/jnr.490340212 · Cited by 204 · see citing works
Fasulo, L., Ugolini, G., Visintin, M., Bradbury, A. M., Brancolini, C., Verzillo, V., Novák, M., & Cattaneo, A. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0750624.x · Cited by 195 · see citing works
Neuronal Apoptosis Induced by β-Amyloid Is Mediated by Caspase-8
Ivins, K. J., Thornton, P. L., Rohn, T. T., & Cotman, C. W. (1999) · Neurobiology of Disease · doi:10.1006/nbdi.1999.0268 · Cited by 187 · see citing works
Phosphorylation of microtubule‐associated protein tau by isoforms of c‐Jun N‐terminal kinase (JNK)
Yoshida, H., Hastie, C. J., McLauchlan, H., Cohen, P., & Goedert, M. (2004) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2004.02479.x · Cited by 185 · see citing works
Activation of caspase-3 in β-amyloid-induced apoptosis of cultured rat cortical neurons
Harada, J., & Sugimoto, M. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01808-9 · Cited by 184 · see citing works
Ferreira, A., Lu, Q., Orecchio, L., & Kosik, K. S. (1997) · Molecular and Cellular Neuroscience · doi:10.1006/mcne.1997.0615 · Cited by 178 · see citing works
Self-citationMarques, C. A., Keil, U., Bonert, A., Steiner, B., Haass, C., Müller, W. E., & Eckert, A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212265200 · Cited by 175 · see citing works
Copani, A., Bruno, V., Battaglia, G., Leanza, G., Pellitteri, R., Russo, A., Stanzani, S., & Nicoletti, F. (1995) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)08600-6 · Cited by 167 · see citing works
Correlation between Caspase Activation and Neurofibrillary Tangle Formation in Alzheimer’s Disease
Rohn, T. T., Head, E., Su, J. H., Anderson, A. J., Bahr, B. A., Cotman, C. W., & Cribbs, D. H. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63957-0 · Cited by 164 · see citing works
Ivins, K. J., Bui, E. T. N., & Cotman, C. W. (1998) · Neurobiology of Disease · doi:10.1006/nbdi.1998.0228 · Cited by 164 · see citing works
Flood, J. F., Morley, J. E., & Roberts, E. R. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.8.3363 · Cited by 164 · see citing works
Ekinci, F. J., Malik, K. U., & Shea, T. B. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.42.30322 · Cited by 161 · see citing works
Ischemic neuronal death in the rat hippocampus: the calpain–calpastatin–caspase hypothesis
Rami, A. (2003) · Neurobiology of Disease · doi:10.1016/s0969-9961(03)00018-4 · Cited by 157 · see citing works
Grynspan, F., Griffin, W. R., Cataldo, A. M., Katayama, S., & Nixon, R. A. (1997) · Brain Research · doi:10.1016/s0006-8993(97)00384-3 · Cited by 156 · see citing works
Ferreira, A., Busciglio, J. A., & Cáceres, A. (1989) · Developmental Brain Research · doi:10.1016/0165-3806(89)90023-0 · Cited by 151 · see citing works
Self-citationPD98059 Prevents Neurite Degeneration Induced by Fibrillar β‐Amyloid in Mature Hippocampal Neurons
Rapoport, M., & Ferreira, A. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0740125.x · Cited by 139 · see citing works
Self-citationMultiple caspases are involved in β‐amyloid‐induced neuronal apoptosis
Allen, J. W., Eldadah, B. A., Huang, X., Knoblach, S. M., & Faden, A. I. (2001) · Journal of Neuroscience Research · doi:10.1002/jnr.1126 · Cited by 127 · see citing works
Tau protein I is essential for amyloid β-protein iduced neurotoxicity
Takashima, A. (1993) · Medical Entomology and Zoology · Cited by 125 · see citing works
Veeranna, Kaji, T., Boland, B., Odrljin, T. M., Mohan, P. S., Basavarajappa, B. S., Peterhoff, C. M., Cataldo, A. M., Rudnicki, A., Amin, N. D., et al. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63342-1 · Cited by 123 · see citing works
Rami, A., Agarwal, R., Botez, G., & Winckler, J. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02301-5 · Cited by 115 · see citing works
Calpain‐Induced Proteolysis of Normal Human Tau and Tau Associated with Paired Helical Filaments
Yang, L., & Ksiezak‐Reding, H. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.009_1.x · Cited by 113 · see citing works
Goslin, K., & Banker, G. A. (1990) · The Journal of Cell Biology · doi:10.1083/jcb.110.4.1319 · Cited by 113 · see citing works
Adamec, E., Mohan, P. S., Vonsattel, J. P., & Nixon, R. A. (2002) · Acta Neuropathologica · doi:10.1007/s00401-002-0528-6 · Cited by 100 · see citing works
m-Calpain (calcium-activated neutral proteinase) in Alzheimer's disease brains
Tsuji, T., Shimohama, S., Kimura, J., & Shimizu, K. (1998) · Neuroscience Letters · doi:10.1016/s0304-3940(98)00348-6 · Cited by 90 · see citing works
Mercken, M. H., Grynspan, F., & Nixon, R. A. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)00590-6 · Cited by 74 · see citing works
Multiple forms of Ca-activated protease from rat brain and muscle.
Zimmerman, U.-J. P., & Schlaepfer, W. W. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)43282-0 · Cited by 71 · see citing works
β-Amyloid-induced activation of Caspase-3 in primary cultures of rat neurons
Marín, N., Romero, B., Bosch‐Morell, F., Llansola, M., Felipo, V., Romá, J., & Romero, F. J. (2000) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(00)00172-x · Cited by 70 · see citing works
Shea, T. B., Spencer, M. J., Beermann, M. L., Cressman, C. M., & Nixon, R. A. (1996) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1996.66041539.x · Cited by 55 · see citing works
Boland, B. (2002) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00060-x · Cited by 38 · see citing works
Imajoh, S., Kawasaki, H., & Suzuki, K. (1987) · The Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a121930 · Cited by 37 · see citing works
Adamec, E., Murrell, J. R., Takao, M., Hobbs, W., Nixon, R. A., Ghetti, B. F., & Vonsattel, J. P. (2002) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(02)00150-8 · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The spectrum of disease in chronic traumatic encephalopathy
McKee, A. C., Stein, T. D., Nowinski, C. J., Stern, R. A., Daneshvar, D. H., Alvarez, V. E., Lee, H.-S., Hall, G., Wojtowicz, S. M., Baugh, C. M., et al. (2013) · Brain · doi:10.1093/brain/aws307 · Cited by 2,098 · see citing works
Reducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model
Roberson, E. D., Scearce-Levie, K., Palop, J. J., Yan, F., Cheng, I. H., Wu, T., Gerstein, H., Yu, G.-Q., & Mucke, L. (2007) · Science · doi:10.1126/science.1141736 · Cited by 1,892 · see citing works
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994 · see citing works
Roles of tau protein in health and disease
Guo, T., Noble, W., & Hanger, D. P. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1707-9 · Cited by 1,003 · see citing works
Morris, M., Maeda, S., Vossel, K., & Mucke, L. (2011) · Neuron · doi:10.1016/j.neuron.2011.04.009 · Cited by 899 · see citing works
Zempel, H., Thies, E., Mandelkow, E., & Mandelkow, E.-M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2357-10.2010 · Cited by 686 · see citing works
“…focused primarily on global effects of A on changes in Tau (e.g., phosphorylation, cleavage) and resulting cell death (Yankner et al., 1989; Mattson, 1990; Busciglio et al., 1995; Park and Ferreira, 2005; King et al., 2006), with less attention to the localized changes due to Tau redistribution.”
BackgroundRoberson, E. D., Halabisky, B., Yoo, J. W., Yao, J., Chin, J., Yan, F., Wu, T., Hamto, P., Devidze, N., Yu, G.-Q., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4152-10.2011 · Cited by 654 · see citing works
The Neuropathology of Chronic Traumatic Encephalopathy
McKee, A. C., Stein, T. D., Kiernan, P. T., & Alvarez, V. E. (2015) · Brain Pathology · doi:10.1111/bpa.12248 · Cited by 585 · see citing works
Zhang, Z., Song, M., Liu, X., Kang, S. S., Kwon, I.-S., Duong, D. M., Seyfried, N. T., Hu, W. T., Liu, Z., Wang, J.-Z., et al. (2014) · Nature Medicine · doi:10.1038/nm.3700 · Cited by 494 · see citing works
The importance of tau phosphorylation for neurodegenerative diseases
Noble, W., Hanger, D. P., Miller, C. C. J., & Lovestone, S. (2013) · Frontiers in Neurology · doi:10.3389/fneur.2013.00083 · Cited by 475 · see citing works
Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies
Brunden, K. R., Trojanowski, J. Q., & Lee, V. M.-Y. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2959 · Cited by 440 · see citing works
Alquezar, C., Arya, S., & Kao, A. W. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2020.595532 · Cited by 367 · see citing works
Tau Protein Is Required for Amyloid β-Induced Impairment of Hippocampal Long-Term Potentiation
Shipton, O. A., Leitz, J. R., Dworzak, J., Acton, C. E. J., Tunbridge, E. M., Denk, F., Dawson, H. N., Vitek, M. P., Wade-Martins, R., Paulsen, O., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.2610-10.2011 · Cited by 315 · see citing works
Development of tau aggregation inhibitors for alzheimer's disease
Bulic, B., Pickhardt, M., Schmidt, B., Mandelkow, E., Waldmann, H., & Mandelkow, E. (2009) · Angewandte Chemie International Edition · doi:10.1002/anie.200802621 · Cited by 286 · see citing works
Structural Principles of Tau and the Paired Helical Filaments of Alzheimer's Disease
Mandelkow, E., Von Bergen, M., Biernat, J., & Mandelkow, E. (2007) · Brain Pathology · doi:10.1111/j.1750-3639.2007.00053.x · Cited by 243 · see citing works
Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies
Sinsky, J., Pichlerova, K., & Hanes, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179207 · Cited by 220 · see citing works
Tau Proteolysis in the Pathogenesis of Tauopathies: Neurotoxic Fragments and Novel Biomarkers
Quinn, J. P., Corbett, N. J., Kellett, K. A. B., & Hooper, N. M. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-170959 · Cited by 170 · see citing works
Degradation of tau protein by autophagy and proteasomal pathways
Wang, Y., & Mandelkow, E. (2012) · Biochemical Society Transactions · doi:10.1042/bst20120071 · Cited by 166 · see citing works
Calpain is required for macroautophagy in mammalian cells
Demarchi, F., Bertoli, C., Copetti, T., Tanida, I., Brancolini, C., Eskelinen, E.-L., & Schneider, C. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200601024 · Cited by 156 · see citing works
Funk, K. E., Thomas, S. N., Schafer, K. N., Cooper, G. L., Liao, Z., Clark, D. J., Yang, A. J., & Kuret, J. (2014) · Biochemical Journal · doi:10.1042/bj20140372 · Cited by 142 · see citing works
Pre‐synaptic C‐terminal truncated tau is released from cortical synapses in Alzheimer's disease
Sokolow, S., Henkins, K. M., Bilousova, T., Gonzalez, B., Vinters, H. V., Miller, C. A., Cornwell, L., Poon, W. W., & Gylys, K. H. (2015) · Journal of Neurochemistry · doi:10.1111/jnc.12991 · Cited by 133 · see citing works
Corsetti, V., Florenzano, F., Atlante, A., Bobba, A., Ciotti, M. T., Natale, F., Della Valle, F., Borreca, A., Manca, A., Meli, G., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv059 · Cited by 129 · see citing works
Thomas, S. N., Funk, K. E., Wan, Y., Liao, Z., Davies, P., Kuret, J., & Yang, A. J. (2012) · Acta Neuropathologica · doi:10.1007/s00401-011-0893-0 · Cited by 123 · see citing works
Ferreira, A., & Bigio, E. H. (2011) · Molecular Medicine · doi:10.2119/molmed.2010.00220 · Cited by 112 · see citing works
Self-citationAmbegaokar, S. S., & Jackson, G. R. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr432 · Cited by 113 · see citing works
“Indeed, calpain A has been shown to cleave tau and is reported to be responsible for producing a 17 kDa fragment that may be a highly toxic tau derivative (211,212).”
BackgroundBernardo, T. C., Marques‐Aleixo, I., Beleza, J., Oliveira, P. J., Ascensão, A., & Magalhães, J. (2016) · Brain Pathology · doi:10.1111/bpa.12403 · Cited by 108 · see citing works
Cleavage of Tau by calpain in Alzheimer's disease: the quest for the toxic 17 kD fragment
Garg, S., Timm, T., Mandelkow, E.-M., Mandelkow, E., & Wang, Y. (2011) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.09.008 · Cited by 103 · see citing works
Tau hyperphosphorylation and deregulation of calcineurin in mouse models of Huntington’s disease
Gratuze, M., Noël, A., Julien, C., Cisbani, G., Milot-Rousseau, P., Morin, F., Dickler, M., Goupil, C., Bezeau, F., Poitras, I., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddu456 · Cited by 65 · see citing works
Calpain-mediated tau fragmentation is altered in Alzheimer’s disease progression
Chen, H.-H., Liu, P., Auger, P., Lee, S.-H., Adolfsson, O., Rey-Bellet, L., Lafrance-Vanasse, J., Friedman, B. A., Pihlgren, M., Muhs, A., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-35130-y · Cited by 51 · see citing works
Neuronal degeneration, synaptic defects, and behavioral abnormalities in tau45-230 transgenic mice
Lang, A. E., Riherd Methner, D. N., & Ferreira, A. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.06.017 · Cited by 35 · see citing works
Self-citationThe metamorphic nature of the Tau protein: dynamic flexibility comes at a cost
Sabbagh, J. J., & Dickey, C. A. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00003 · Cited by 31 · see citing works
“Cleavage by either of these proteases produces truncated tau forms which are more neurotoxic than full-length tau (Chung et al., 2001; Park and Ferreira, 2005).”
BackgroundProtein-Protein Interactions and Aggregation Inhibitors in Alzheimer’s Disease
Ganeshpurkar, A., Swetha, R., Kumar, D., Gangaram, G. P., Singh, R., Gutti, G., Jana, S., Kumar, D., Kumar, A., & Singh, S. K. (2019) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026619666190304153353 · Cited by 30 · see citing works
Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease
Chimal-Juárez, E., Patel, H., Jury-Garfe, N., Dabin, L. C., Vidal, R., Kim, J., & Lasagna-Reeves, C. A. (2026) · bioRxiv · doi:10.64898/2026.05.12.724684
- Authors
- Park, S.-Y., & Ferreira, A.
- Affiliations
- Northwestern University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2005-06-01
- Volume
- 25
- Issue
- 22
- Pages
- 5365-5375
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC1352316
- OpenAlex
- W2000655392
- Cited by
- 262
- References
- 65
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 3 · 2023: 10 · 2022: 7 · 2021: 15 · 2020: 8 · 2019: 11 · 2018: 15 · 2017: 9 · 2016: 13 · 2015: 13 · 2014: 24 · 2013: 11 · 2012: 23
- FWCI
- 7.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS039080, NS 39080)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Calpain Protease Function and Regulation
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, amyloid-beta, neurotoxicity, calpain-1, tau cleavage, hippocampal neurons, neurite degeneration, neuronal cell death, caspases
- MeSH terms
- Alzheimer Disease, Animals, Calpain, Cells, Cultured, Cricetulus, Enzyme Activation, Cricetinae, Hippocampus, Hydrolysis, Molecular Weight, Nerve Degeneration, Neurons, Peptide Fragments, Phosphorylation, Amyloid beta-Peptides, CHO Cells, tau Proteins, Caspases, Rats, Caspase 3, Caspase Inhibitors
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
