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Papers In Press, published online ahead of print June 23, 2003
J. Biol. Chem, 10.1074/jbc.M301406200
Submitted on February 10, 2003
Revised on June 23, 2003
Accepted on June 22, 2003

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

Neurology and Pharmacology; Neurobiology Research Laboratory, University of Kansas Medical School; Veterans Affairs Medical Center, Kansas City, MO 64128

Corresponding Author: bfestoff{at}kumc.edu

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 (PARs), which was followed by delayed synaptophysin reduction and apoptotic neuronal death. Mechanistic study revealed that a persistent thrombin signaling via PAR4 and prolonged downstream p44/42 mitogen-activated 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 sea change shifts in therapeutic paradigms.


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