%0 Journal Article %J J Alzheimers Dis %D 2018 %T Free Heme and Amyloid-β: A Fatal Liaison in Alzheimer's Disease. %A Chiziane, Elisabeth %A Telemann, Henriette %A Krueger, Martin %A Adler, Juliane %A Arnhold, Jürgen %A Alia, A %A Flemmig, Jörg %K Alzheimer Disease %K Amino Acid Sequence %K Amyloid %K Amyloid beta-Peptides %K Animals %K Brain %K Disease Models, Animal %K Heme %K Humans %K Hydrogen Peroxide %K Mice %K Mice, Transgenic %K Oxidation-Reduction %K Peptide Fragments %K Peroxidases %X

While the etiology of Alzheimer's disease (AD) is still unknown, an increased formation of amyloid-β (Aβ) peptide and oxidative processes are major pathological mechanism of the disease. The interaction of Aβ with free heme leads to the formation of peroxidase-active Aβ-heme complexes. However, enzyme-kinetic data and systematic mutational studies are still missing. These aspects were addressed in this study to evaluate the role of Aβ-heme complexes in AD. The enzyme-kinetic measurements showed peroxidase-specific pH- and H2O2-dependencies. In addition, the enzymatic activity of Aβ-heme complexes constantly increased at higher peptide excess. Moreover, the role of the Aβ sequence for the named enzymatic activity was tested, depicting human-specific R5, Y10, and H13 as essential amino acids. Also by studying Y10 as an endogenous peroxidase substrate for Aβ-heme complexes, ratio-specific effects were observed, showing an optimal dityrosine formation at an about 40-fold peptide excess. As dityrosine formation promotes Aβ fibrillation while free heme disturbs protein aggregation, we also investigated the effect of Aβ-heme complex-derived peroxidase activity on the formation of Aβ fibrils. The fluorescence measurements showed a different fibrillation behavior at strong peroxidase activity, leading also to altered fibril morphologies. The latter was detected by electron microscopy. As illustrated by selected in vivo measurements on a mouse model of AD, the disease is also characterized by Aβ-derived microvessel destructions and hemolytic processes. Thus, thrombo-hemorrhagic events are discussed as a source for free heme in brain tissue. In summary, we suggest the formation and enzymatic activity of Aβ-heme complexes as pathological key features of AD.

%B J Alzheimers Dis %V 61 %P 963-984 %8 2018 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/29332049?dopt=Abstract %R 10.3233/JAD-170711