HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 7, 5145-5153, February 18, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/7/5145    most recent M409234200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal 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 Google Scholar Google Scholar Articles by Arai, T. Articles by McGeer, P. L. Search for Related Content PubMed PubMed Citation Articles by Arai, T. Articles by McGeer, P. L. Social Bookmarking                      What's this?

Proteolysis of Non-phosphorylated and Phosphorylated Tau by Thrombin^*

Tetsuaki Arai, Jian-Ping Guo, and Patrick L. McGeer

From the Department of Psychiatry, Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

The microtubule-associated protein tau aggregates intracellularly by unknown mechanisms in Alzheimer's disease and other tauopathies. A contributing factor may be a failure to break down free cytosolic tau, thus creating a surplus for aggregation, although the proteases that degrade tau in brain remain unknown. To address this issue, we prepared cytosolic fractions from five normal human brains and from perfused rat brains and incubated them with or without protease inhibitors. D-Phenylalanyl-L-prolylarginyl chloromethyl ketone, a thrombin-specific inhibitor, prevented tau breakdown in these fractions, suggesting that thrombin is a brain protease that processes tau. We next exposed human recombinant tau to purified human thrombin and analyzed the fragments by N-terminal sequencing. We found that thrombin proteolyzed tau at multiple arginine and lysine sites. These include Arg¹⁵⁵–Gly¹⁵⁶, Arg²⁰⁹–Ser²¹⁰, Arg²³⁰–Thr²³¹, Lys²⁵⁷–Ser²⁵⁸, and Lys³⁴⁰–Ser³⁴¹ (numbering according to the longest human tau isoform). Temporally, the initial cleavage occurred at the Arg¹⁵⁵–Gly¹⁵⁶ bond. Proteolysis of the resultant C-terminal tau fragment then proceeded bidirectionally. When tau was phosphorylated by glycogen synthase kinase-3, most of these proteolytic processes were inhibited, except for the first cleavage at the Arg¹⁵⁵–Gly¹⁵⁶ bond. Furthermore, paired helical filament tau prepared from Alzheimer's disease brain was more resistant to thrombin proteolysis than following dephosphorylation by alkaline phosphatase. The results suggest a possible role for thrombin in proteolysis of tau under physiological and/or pathological conditions in human brains. They are consistent with the hypothesis that phosphorylation of tau inhibits proteolysis by thrombin or other endogenous proteases, leading to aggregation of tau into insoluble fibrils.

Received for publication, August 12, 2004 , and in revised form, October 12, 2004.

^* This work was supported by grants from the Japan Foundation for Aging and Health, the Jack Brown and Family Alzheimer's Disease Research Fund, and the George Hodgson Estate. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence and reprint requests should be addressed: Dept. of Psychiatry, Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada. Tel.: 604-822-7377; Fax: 604-822-7086; E-mail: mcgeerpl{at}interchange.ubc.ca.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				I. Ferrer, G. Santpere, and F. W. van Leeuwen Argyrophilic grain disease Brain, June 1, 2008; 131(6): 1416 - 1432. [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]

				K. N. Green, H. Martinez-Coria, H. Khashwji, E. B. Hall, K. A. Yurko-Mauro, L. Ellis, and F. M. LaFerla Dietary Docosahexaenoic Acid and Docosapentaenoic Acid Ameliorate Amyloid-{beta} and Tau Pathology via a Mechanism Involving Presenilin 1 Levels J. Neurosci., April 18, 2007; 27(16): 4385 - 4395. [Abstract] [Full Text] [PDF]

				J.-P. Guo, T. Arai, J. Miklossy, and P. L. McGeer From the Cover: Abeta and tau form soluble complexes that may promote self aggregation of both into the insoluble forms observed in Alzheimer's disease PNAS, February 7, 2006; 103(6): 1953 - 1958. [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]