Interaction of amyloid β peptides with redox active heme cofactor: Relevance to Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder that has generally been associated with the accumulation of amyloid beta (Aβ) peptides and the formation of partially reduced oxygen species (PROS) catalyzed by redox active transition metal bound Aβ active sites in the brain. Heme binding to these Aβ peptides has opened up a new direction in the field of AD. This review illustrates the role of heme in AD and discusses the nature of active site environment of the heme-Aβ complexes. The peroxidase activity of the heme-Aβ complexes has been discussed, highlighting the significance of 2nd sphere residues. The Aβ peptides can simultaneously bind heme and Cu retaining the electronic, chemical and electrochemical properties of the individual metal sites. The heme-Aβ, Cu-Aβ and both heme and Cu bound Aβ (heme-Cu-Aβ) complexes exhibit harmful PROS generating properties and the redox active Tyr10 residue has been demonstrated to play a significant role in PROS formation. Finally some possible therapeutics and their limitations relevant to AD are discussed.

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► His13 of Aβ peptide binds heme.
► The Arg5 residue H-bonds with the axial water ligand of heme-Aβ, lowering its pKa and making heme-Aβ complexes function as peroxidases.
► Aβ peptides can bind to both heme and Cu cofactors simultaneously.
► Tyr10 residue acts as a source of electrons during PROS formation.