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

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.

Dystrophic microglia in late‐onset Alzheimer's disease

“…Furthermore, iron has been linked to the aggregation and oxidation of amyloid (Dong et al, 2003;Head et al, 2001;Lovell, Robertson, Teesdale, Campbell, & Markesbery, 1998), which also contributes to progression of microglial dystrophy. Thus, free iron and amyloid together create a toxic brew that greatly increases oxidative stress on all brain cells, including microglia (Chiziane et al, 2018).…”

Relationships between Mitochondrial Dysfunction and Neurotransmission Failure in Alzheimer’s Disease

“…In the cytoplasm of AD neurones, haem-Aβ complex forms when haem is released from mitochondria [196]. Under high peroxidative stress, the haem-Aβ complex breaks down 5-HT to dihydroxytryptamine or tryptamine-4,5-dione [79,80,197], which limits the neuroactivity of the serotoninergic system in AD.…”

“…In addition, mitochondrial-related oxidative stress can be exacerbated by the intramitochondrial Aβ accumulation, Aβ-binding alcohol dehydrogenase [ 25 , 77 , 78 ], and peroxidation of haem-Aβ complexes under H 2 O 2 [ 79 , 80 ]. The oxidative stress then triggers lipid peroxidation [ 81 , 82 ] and protein oxidation [ 74 , 83 , 84 ], which in turn, lead to oxidative dysfunction of key ETC complexes [ 85 ], and PDHC and KDGHC of the TCA cycle [ 86 - 88 ].…”

Increased expression of heme-binding protein 1 early in Alzheimer's disease is linked to neurotoxicity

“…Dysregulation of proteins linked to heme metabolism has been reported in AD (Hani Atamna & Frey, 2004; Schipper et al, 1995). Moreover, Aβ can form a complex with heme which possesses strong peroxidase and superoxide activities that can contribute to oxidative stress and cytotoxicity during AD (Atamna and Boyle, 2006; Chiziane et al, 2018; Ghosh et al, 2015). Accumulation of Aβ around brain vasculature results in cerebral amyloid angiopathy (CAA), microvessel destruction and leakage of free heme into brain tissue (Chiziane et al, 2018).…”