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J. Biol. Chem., Vol. 278, Issue 39, 37681-37689, September 26, 2003

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Rapid Tau Aggregation and Delayed Hippocampal Neuronal Death Induced by Persistent Thrombin Signaling^*

Zhiming Suo  , Min Wu , Bruce A. Citron  , Robert E. Palazzo ** and Barry W. Festoff   || 

From the Neurobiology Research Laboratory, Veterans Affairs Medical Center, Kansas City, Missouri 64128, the Departments of Neurology and ^||Pharmacology, Toxicology and Therapeutics, University of Kansas School of Medicine, Kansas City, Kansas 66170, and the ^**Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045

Tau hyperphosphorylation, leading to self-aggregation, is widely held to underlie the neurofibrillary degeneration found in Alzheimer's disease (AD) and other tauopathies. However, it is unclear exactly what environmental factors may trigger this pathogenetic tau hyperphosphorylation. From several perspectives, the coagulation serine protease, thrombin, has been implicated in AD and activates several different protein kinase pathways but has not previously been shown how it may contribute to AD pathogenesis. Here we report that nanomolar thrombin induced rapid tau hyperphosphorylation and aggregation in murine hippocampal neurons via protease-activated receptors, which was followed by delayed synaptophysin reduction and apoptotic neuronal death. Mechanistic study revealed that a persistent thrombin signaling via protease-activated receptor 4 and prolonged downstream p44/42 mitogenactivated protein kinase activation are at least in part responsible. These results pathogenetically linked thrombin to subpopulations of AD and other tauopathies associated with cerebrovascular damage. Such knowledge may be instrumental in transforming therapeutic paradigms.

Received for publication, February 10, 2003 , and in revised form, June 6, 2003.

^* This work was supported by grants from the Medical Research and Development Service, Department of Veterans Affairs (to Z. S., B. A. C., and B. W. F.), the Missouri Alzheimer's Research Fund (to Z. S.), the Alzheimer's Association (to B. A. C.), the Alzheimer's Association (to B. A. C.), and the Midwest Biomedical Research Foundation. 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 should be addressed: Neurobiology Research Laboratory (151), Veterans Affairs Medical Center, Kansas City, MO 64128. Tel.: 816-861-4700 (ext. 7079); Fax: 816-922-3375; E-mail: bfestoff{at}kumc.edu.

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