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

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.

Cell Death and Learning Impairment in Mice Caused by in Vitro Modified Pro-NGF Can Be Related to Its Increased Oxidative Modifications in Alzheimer Disease

“…36 MGO, GO, and MDA are some of the most reactive compounds in terms of formation of tau dimers and higher molecular-weight oligomers. These modifications have been suggested as accelerating tangle formation in vivo, and as a consequence 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 AD.…”

“…These modifications have been suggested as accelerating tangle formation in vivo, and as a consequence 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 AD. 36 The entorhinal cortex is the earliest cortical region affected by AD (stages I/II), followed by the hippocampus (stages III/IV). 20 In our study we observed a clear augmentation in the levels of nonenzymatic oxidative modifications in pro-NGF molecules in hippocampus and entorhinal cortex samples from AD-affected brains.…”

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

“…Acrolein has been reported to form a bis-adduct with lysine residues, named N ε -(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine) [33]. The electrophilic α,β-unsaturated carbonyl moiety is retained in FDP-lysine, allowing it to react further with sulfhydryl compounds, such as GSH [96], or other nucleophilic sites in proteins under formation of cross-links [97]. FDP-lysine has been detected immunochemically in brain tissue from Alzheimer's disease patients, particularly in neurofibrillary tangles of the microtubule-associated protein Tau [98].…”

Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer’s disease

“…Another approach to the inhibition of tangle formation might be the inhibition of tau crosslinking e.g. by advanced glycation endproducts by the use of anti-glycation agents (Kuhla et al 2007;Krautwald et al 2010;. Furthermore, it has been suggested that microtubule ( However, with growing uncertainty of the therapeutic potential of drugs targeting amyloid and tau, other novel therapies have recently been proposed, including those targeting glycation, oxidative stress and inflammation ).…”