Alzheimer’s Disease: A Heme–Aβ Perspective

Abstract

CONSPECTUS: Redox active iron is utilized in biology for various electron transfer and catalytic reactions essential for life, yet this same chemistry mediates the formation of partially reduced oxygen species (PROS). Oxidative stress derived from the iron accumulated in the amyloid plaques originating from amyloid β (Aβ) peptides and neurofibrillary tangles derived from hyperphosphorylated tau proteins has been implicated in the pathogenesis of Alzheimer's disease (AD). Altered heme homeostasis leading to dysregulation of expression of heme proteins and heme deposits in the amyloid plaques are characteristic of the AD brain. However, the pathogenic significance of heme in neurodegeneration in AD has been unappreciated due to the lack of detailed understanding of the chemistry of the interaction of heme and Aβ peptides. As a result, the biochemistry and biophysics of heme complexes of Aβ peptides (heme−Aβ) remained largely unexplored. In this Account, we discuss the active site environment of heme bound Aβ complexes, which involves three amino acid residues unique in mammalian Aβ (Arg5, Tyr10, and His13) and missing in Aβ from rodents, which do not get affected by AD. The histidine residue binds heme, while the arginine and the tyrosine act as key second sphere residues of the heme−Aβ active site that play a crucial role in its reactivity. Generation of PROS, enhanced peroxidase activity, and oxidation of neurotransmitters such as serotonin (5-HT) are all found to be catalyzed by heme−Aβ in in vitro assays, and these reactivities can potentially be linked to the observed neuropathologies in AD brain. Association of Cu with heme−Aβ leads to the formation of heme−Cu−Aβ. The heme−Cu−Aβ complex produces a greater amount of PROS than reduced heme−Aβ or Cu−Aβ alone. Nitric oxide (NO), a signaling molecule, is found to ameliorate the detrimental effects of heme−Aβ and Cu bound heme−Aβ complexes by detaching heme from the heme−Aβ complex and releasing it into the environment solution. Heme−Aβ complexes show fast electron transfer with oxidized cytochrome c and rapid heme transfer with apomyoglobin and aponeuroglobin. NO, cytochrome c, and apoglobins can all lead to reduction in PROS generated by reduced heme−Aβ. Synthetic analogues of heme, offering a hydrophobic distal environment, have been used to trap oxygen bound intermediates, which provides insight into the mechanism of PROS generation by reduced heme−Aβ. Artificial constructs of Aβ on nonbiological platforms are used not only to stabilize metastable and physiologically relevant large and small amyloid aggregates but also to monitor the interaction of various drug candidates with heme and Cu bound Aβ aggregates, representing a tractable avenue for testing therapeutic agents targeting metals and cofactors in AD.

Hemin and bile pigments are the secondary structure regulators of intrinsically disordered antimicrobial peptides

“…[51][52][53] Moreover, heme binding to amyloid-β peptides and the altered heme homeostasis in Alzheimer's disease have also been demonstrated. 50,54 There are serious lacuna, however, in understanding the chemical nature of hemin-peptide and bile pigment-peptide interactions, which instigated us to study how these compounds affect the secondary structure of intrinsically disordered model peptides. Our work supplies direct spectroscopic evidences on the complex, sequence-dependent, significantly different structure modifying ability of hemin and its natural derivatives mediated by hydrophobic (Trp-porphyrin) and most likely ionic (Lys/Arg-propionate) forces.…”

The Amyloid‐β Peptide in Amyloid Formation Processes: Interactions with Blood Proteins and Naturally Occurring Metal Ions

“…One of the residues of H13 and H14 in Aβ has been suggested as a heme‐binding‐ligand . Peroxidase reactions promoted from Aβ‐heme complexes are facilitated by the presence of N‐terminal residues R5 and Y10, residues that are absent in the Aβ peptide naturally expressed in rodents . Copper ion interaction is not compromised when simultaneously present with heme molecules .…”

“…[71] Peroxidase reactions promoted from Ab-heme complexes are facilitated by the presence of N-terminal residues R5 and Y10, residues that are absent in the Ab peptide naturally expressed in rodents. [72] Copper ion interaction is not compromised when simultaneously present with heme molecules. [73] Ab fibril formation is inhibited in the presence of heme, and mutational studies indicate contributions from both iron and porphyrin interactions.…”

Metallotexaphyrins as MRI-Active Catalytic Antioxidants for Neurodegenerative Disease: A Study on Alzheimer’s Disease

“…The interaction of hemin and other water-soluble phthalocyanines, corroles, and porphyrins with Ab has been noted. [29][30][31][32] We thus envisaged that coupling the Ab-recognition properties of metalloporphyrins with the biological activity of metallotexaphyrins would allow for MRI recognition of Ab species with attendant utility as a potential metalloantioxidant therapeutic ( Figure 2). As detailed further below, we have found that metallotexaphyrins, in particular MMn, interact with amyloid constructs, as inferred from ultraviolet-visible (UV-vis), fluorescence, and circular dichroism (CD) spectroscopies, as well as MRI studies.…”