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J Alzheimers Dis. 2018;61(3):963-984. doi: 10.3233/JAD-170711.

Free Heme and Amyloid-β: A Fatal Liaison in Alzheimer's Disease.

Author information

1
Institute for Medical Physics and Biophysics, Medical Faculty, Leipzig University, Leipzig, Germany.
2
Institute for Anatomy, Medical Faculty, Leipzig University, Leipzig, Germany.
3
Leiden Institute of Chemistry, Faculty of Science, Leiden University, Leiden, The Netherlands.

Abstract

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.

KEYWORDS:

Alzheimer’s disease; Aβ-heme complexes; amyloid-β fibrillation; amyloid-β toxicity; free heme; hemolysis; peroxidase activity

PMID:
29332049
DOI:
10.3233/JAD-170711
[Indexed for MEDLINE]

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