Heme interactions with Aβ, Tau and Prion protein in neurodegeneration: coordination chemistry at the crossroads of oxidative stress and protein aggregation

Heme is a cofactor that plays a significant in vivo role in oxygen transport, electron transfer, enzymatic reactions and regulation. Heme is usually bound by hemoproteins, but a small percentage exists in its free form as it is involved in signaling processes. Free heme can accumulate under pathological conditions such as homeostasis dysregulation, traumatic brain injury or intracerebral hemorrhage. The increase in free heme level can lead to the insurgence of neurodegenerative diseases, since heme dynamics can influence the accumulation of misfolded proteins and the rise of oxidative stress through Fenton-like chemistry. Indeed, heme exhibits high binding af finity for neuronal peptides and proteins such as amyloid-β peptides, tau-protein and prion protein; these teractions can alter peptide and protein conformations (accentuating their aggregation) and enhance the peroxidase-like activity of free heme, thus promoting oxidative and nitrative stress. The aim of this review is to comprehensively analyze the work done on the characterization of the binding between heme and neuronal proteins, as well as the reactivity of the complexes formed, to shed light on the correlation between heme dysregulation and the insurgence of neurodegenerative diseases.