QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, June 1, 2005, 25(22):5365-5375; doi:10.1523/JNEUROSCI.1125-05.2005

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (30) Citing Articles via Google Scholar Google Scholar Articles by Park, S.-Y. Articles by Ferreira, A. Search for Related Content PubMed PubMed Citation Articles by Park, S.-Y. Articles by Ferreira, A. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Alzheimer's Disease

 Previous Article  |  Next Article 

Neurobiology of Disease
The Generation of a 17 kDa Neurotoxic Fragment: An Alternative Mechanism by which Tau Mediates -Amyloid-Induced Neurodegeneration

So-Young Park and Adriana Ferreira

Department of Cell and Molecular Biology, Feinberg School of Medicine, and Institute for Neuroscience, Northwestern University, Chicago, Illinois 60611

Recently, we have shown that the microtubule-associated protein tau is essential for -amyloid (A)-induced neurotoxicity in hippocampal neurons. However, the mechanisms by which tau mediates A-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 A 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 A-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 A-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 A-induced neurotoxicity.

Key words: Alzheimer; apoptosis; degeneration; hippocampus; neurotoxicity; proteolysis; amyloid

---

Received Dec 8, 2004; accepted April 20, 2005.

This article has been cited by other articles:

				K. J. Rosenberg, J. L. Ross, H. E. Feinstein, S. C. Feinstein, and J. Israelachvili Complementary dimerization of microtubule-associated tau protein: Implications for microtubule bundling and tau-mediated pathogenesis PNAS, May 27, 2008; 105(21): 7445 - 7450. [Abstract] [Full Text] [PDF]

				K. Eckermann, M.-M. Mocanu, I. Khlistunova, J. Biernat, A. Nissen, A. Hofmann, K. Schonig, H. Bujard, A. Haemisch, E. Mandelkow, et al. The beta-Propensity of Tau Determines Aggregation and Synaptic Loss in Inducible Mouse Models of Tauopathy J. Biol. Chem., October 26, 2007; 282(43): 31755 - 31765. [Abstract] [Full Text] [PDF]

				Y. P. Wang, J. Biernat, M. Pickhardt, E. Mandelkow, and E.-M. Mandelkow Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model PNAS, June 12, 2007; 104(24): 10252 - 10257. [Abstract] [Full Text] [PDF]

				B. Bandyopadhyay, G. Li, H. Yin, and J. Kuret Tau Aggregation and Toxicity in a Cell Culture Model of Tauopathy J. Biol. Chem., June 1, 2007; 282(22): 16454 - 16464. [Abstract] [Full Text] [PDF]

				E. D. Roberson, K. Scearce-Levie, J. J. Palop, F. Yan, I. H. Cheng, T. Wu, H. Gerstein, G.-Q. Yu, and L. Mucke Reducing Endogenous Tau Ameliorates Amyloid {beta}-Induced Deficits in an Alzheimer's Disease Mouse Model Science, May 4, 2007; 316(5825): 750 - 754. [Abstract] [Full Text] [PDF]

				F. Demarchi, C. Bertoli, T. Copetti, I. Tanida, C. Brancolini, E.-L. Eskelinen, and C. Schneider Calpain is required for macroautophagy in mammalian cells J. Cell Biol., November 20, 2006; 175(4): 595 - 605. [Abstract] [Full Text] [PDF]

				B. L. Kelly and A. Ferreira beta-Amyloid-induced Dynamin 1 Degradation Is Mediated by N-Methyl-D-Aspartate Receptors in Hippocampal Neurons J. Biol. Chem., September 22, 2006; 281(38): 28079 - 28089. [Abstract] [Full Text] [PDF]

				Y. H. Chong, Y. J. Shin, E. O. Lee, R. Kayed, C. G. Glabe, and A. J. Tenner ERK1/2 Activation Mediates Abeta Oligomer-induced Neurotoxicity via Caspase-3 Activation and Tau Cleavage in Rat Organotypic Hippocampal Slice Cultures J. Biol. Chem., July 21, 2006; 281(29): 20315 - 20325. [Abstract] [Full Text] [PDF]

				G. Amadoro, M. T. Ciotti, M. Costanzi, V. Cestari, P. Calissano, and N. Canu From the Cover: NMDA receptor mediates tau-induced neurotoxicity by calpain and ERK/MAPK activation PNAS, February 21, 2006; 103(8): 2892 - 2897. [Abstract] [Full Text] [PDF]

				C. Quiniou, F. Sennlaub, M. H. Beauchamp, D. Checchin, I. Lahaie, S. Brault, F. Gobeil Jr., M. Sirinyan, A. Kooli, P. Hardy, et al. Dominant Role for Calpain in Thromboxane-Induced Neuromicrovascular Endothelial Cytotoxicity J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 618 - 627. [Abstract] [Full Text] [PDF]

				I. Khlistunova, J. Biernat, Y. Wang, M. Pickhardt, M. von Bergen, Z. Gazova, E. Mandelkow, and E.-M. Mandelkow Inducible Expression of Tau Repeat Domain in Cell Models of Tauopathy: AGGREGATION IS TOXIC TO CELLS BUT CAN BE REVERSED BY INHIBITOR DRUGS J. Biol. Chem., January 13, 2006; 281(2): 1205 - 1214. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help