title: Aβ interacts with both the iron center and the porphyrin ring of heme: mechanism of heme's action on Aβ aggregation and disaggregation.
abstract: Amyloid β peptide (Aβ) aggregation is a pathological hallmark of Alzheimer's disease (AD). Modulation of the self-assembly processes, therefore, is thought to be an attractive strategy for the prevention and treatment of AD. Interestingly, heme has been found to inhibit Aβ aggregation and even dismantle Aβ aggregates. However, the mechanism remains unresolved. Recent research has shown that heme binds preferentially to the His(13) residue of Aβ with the iron center, while the hydrophobic domain of Aβ is also able to bind to heme. Herein, absorption spectrometric, Thioflavin T fluorescence, and circular dichroism spectroscopic and transmission electron microscopic measurements revealed that the iron center is not required for the inhibition of Aβ aggregation but do influence the binding affinity of heme toward Aβ and the dismantlement rate and degree of the Aβ aggregates. By studying the interaction of different truncated or mutated Aβ peptides with heme or protoporphyrin, we further found that the porphyrin ring of heme is implicated to interact preferentially with the Phe(19) residue, facilitating the binding of heme to Aβ and disturbing the interstrand aromatic interaction between the Phe residues, which is crucial for Aβ fibrillation. These findings open new avenues in the understanding of the interaction between the heme and Aβ and the pathways for modulation of Aβ aggregation and disaggregation, which would be helpful in designing therapeutic strategies against AD.
authors.affiliation: Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, Hubei 430074, People's Republic of China.
authors.forename: Can
authors.initials: C
authors.lastname: Yuan
authors.forename: Zhonghong
authors.initials: Z
authors.lastname: Gao
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D002942:Circular Dichroism; D006418:Heme / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009195:Peroxidase / Q000378:metabolism; D011166:Porphyrins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D011166:Porphyrins; D006418:Heme; D007501:Iron; D009195:Peroxidase