Effect of pseudophosphorylation and cross-linking by lipid peroxidation and advanced glycation end product precursors on Tau aggregation and filament formation

Kuhla, B, Haase, Cathleen, Flach, Katharina, Luth, Hans-Joachim, Arendt, Thomas, and Muench, Gerald (2007) Effect of pseudophosphorylation and cross-linking by lipid peroxidation and advanced glycation end product precursors on Tau aggregation and filament formation. Journal of Biological Chemistry, 282 (10). pp. 6984-6991.

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Abstract

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.

Item ID: 2214
Item Type: Article (Refereed Research - C1)
Keywords: advanced glycation end products; Tau aggregation; crosslinking; Alzheimer's
Additional Information:

Reproduced with permission from American Society for Biochemistry and Molecular Biology.

ISSN: 1083-351X
Date Deposited: 07 May 2009 01:21
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1109 Neurosciences > 110903 Central Nervous System @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920111 Nervous System and Disorders @ 100%
Citation Count from Web of Science Web of Science 33
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