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Alzheimer's Disease: A Heme-Aβ Perspective
Chandradeep Ghosh1, Manas Seal1, Soumya Mukherjee1
1Department of Inorganic Chemistry, Indian Association for the Cultivation of Science , Jadavpur, Kolkata 700032, India.
Accounts of Chemical Research
|August 8, 2015
Summary
Alzheimer's disease involves iron and heme in amyloid plaques, leading to oxidative stress. This study explores heme-amyloid beta interactions, revealing mechanisms for neurodegeneration and potential therapeutic targets.
Area of Science:
- Biochemistry and Neurodegeneration
- Metalloprotein Chemistry and Disease Pathogenesis
Background:
- Redox-active iron chemistry is crucial for life but also generates harmful partially reduced oxygen species (PROS).
- Iron accumulation in amyloid plaques and neurofibrillary tangles is linked to Alzheimer's disease (AD) pathogenesis.
- Altered heme homeostasis and heme deposits in amyloid plaques are characteristic of AD brains, yet their role in neurodegeneration is poorly understood.
Purpose of the Study:
- To explore the biochemistry and biophysics of heme complexes with amyloid-beta (Aβ) peptides (heme-Aβ).
- To understand the active site chemistry of heme-Aβ and its role in generating reactive oxygen species and neurotransmitter oxidation.
- To investigate the influence of copper (Cu) and nitric oxide (NO) on heme-Aβ reactivity and explore therapeutic strategies.
Main Methods:
- Characterization of the heme-Aβ active site, including unique amino acid residues (Arg5, Tyr10, His13) in mammalian Aβ.
- In vitro assays to assess the catalytic activity of heme-Aβ in generating PROS, peroxidase activity, and neurotransmitter oxidation.
- Studies on the formation and reactivity of heme-Cu-Aβ complexes and the effects of nitric oxide (NO), cytochrome c, and apoglobins.
Main Results:
- The heme-Aβ active site, involving His13 for heme binding and Arg5/Tyr10 for second-sphere interactions, dictates its reactivity.
- Heme-Aβ catalyzes the generation of PROS, enhances peroxidase activity, and oxidizes neurotransmitters like serotonin (5-HT).
- Copper significantly increases PROS generation in heme-Cu-Aβ complexes; nitric oxide ameliorates detrimental effects by detaching heme.
Conclusions:
- Heme-Aβ complexes exhibit catalytic activities that can contribute to neurodegeneration observed in Alzheimer's disease.
- The interaction of heme with Aβ peptides, modulated by metals like copper and signaling molecules like NO, offers insights into AD pathogenesis.
- Artificial constructs and studies of heme-Aβ interactions provide avenues for developing therapeutic agents targeting metal ions and cofactors in AD.
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