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J. Biol. Chem., Vol. 282, Issue 10, 6984-6991, March 9, 2007

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Effect of Pseudophosphorylation and Cross-linking by Lipid Peroxidation and Advanced Glycation End Product Precursors on Tau Aggregation and Filament Formation^*

Björn Kuhla¹², Cathleen Haase^¶||1, Katharina Flach^||, Hans-Joachim Lüth^||, Thomas Arendt^||, and Gerald Münch^**

From the Nutritional Physiology Unit "Oskar Kellner," Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany, ^¶Research Center Rossendorf Department of Radiopharmaceutical Biology, Institute of Radiopharmacy, P.O. Box 510119, D-01314 Dresden, Germany, Neuroimmunological Cell Biology Unit, Interdisciplinary Center for Clinical Research (IZKF) Leipzig, Inselstrasse 22, 04103 Leipzig, Germany, ^||Department of Neuroanatomy, Paul-Flechsig-Institute, Jahnallee 59, 04107 Leipzig, Germany, and ^**Comparative Genomics Centre and Department of Biochemistry and Molecular Biology, James Cook University, Townsville 4811, Australia

Accumulation of hyperphosphorylated Tau protein as paired helical filaments in pyramidal neurons is a major hallmark of Alzheimer disease. Besides hyperphosphorylation, other modifications of the Tau protein, such as cross-linking, are likely to contribute to the characteristic features of paired helical filaments, including their insolubility and resistance against proteolytic degradation. In this study, we have investigated whether the four reactive carbonyl compounds acrolein, malondialdehyde, glyoxal, and methylglyoxal accelerate the formation of Tau oligomers, thioflavin T-positive aggregates, and fibrils using wild-type and seven pseudophosphorylated mutant Tau proteins. Acrolein and methylglyoxal were the most reactive compounds followed by glyoxal and malondialdehyde in terms of formation of Tau dimers and higher molecular weight oligomers. Furthermore, acrolein and methylglyoxal induced the formation of thioflavin T-fluorescent aggregates in a triple pseudophosphorylation-mimicking mutant to a slightly higher degree than wild-type Tau. Analysis of the Tau aggregates by electron microscopy study showed that formation of fibrils using wild-type Tau and several Tau mutants could be observed with acrolein and methylglyoxal but not with glyoxal and malondialdehyde. Our results suggest that reactive carbonyl compounds, particularly methylglyoxal and acrolein, could accelerate tangle formation in vivo and that this process could be slightly accelerated, at least in the case of methylglyoxal and acrolein, by hyperphosphorylation. Interference with the formation or the reaction of these reactive carbonyl compounds could be a promising way of inhibiting tangle formation and neuronal dysfunction in Alzheimer disease and other tauopathies.

Received for publication, October 10, 2006 , and in revised form, October 30, 2006.

^* This work was supported by the Interdisziplinäre Zentrum für Klinische Forschung Leipzig at the Faculty of Medicine of the Universität Leipzig (01KS9504, Project N1 and C24), the Hirnliga e.V. (to B. K.), and the Deutsche Forschungsgemeinschaft (HO-2368/1-1, Max Holzer), and a merit research grant by James Cook University (to G. M.). 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.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Research Institute for the Biology of Farm Animals, Nutritional Physiology Unit "Oskar Kellner," Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany. Tel.: 49-38205-68695; Fax: 49-38205-68652; E-mail: b.kuhla{at}fbn-dummerstorf.de.

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