Molecular mechanism of recognition of different forms of the amyloid-beta peptide by Bapineuzumab. A QM/MM study.

GUTIERREZ, LUCAS; PERUCHENA, NELIDA; VETTORAZZI, MARCELA; ENRIZ, RICARDO

Santiago de Chile

Conferencia; Congress of the World Association of Theoretical and Computational Chemists; 2014

WATOC

Aneurodegenerative disease in humans. It is a genetically complex, slowly progressive, and irreversible disease ofthe brain. Besides, it is one of the most common causes ofmental deterioration in elderly people, accounting for around50%-60% of the overall cases of dementia among persons over65 years of age. Currently, it is known that amyloid-beta (Aβ)peptides form soluble oligomers, which are key pathogenicstructures in AD. Thus, the soluble Aβ oligomers represent anattractive therapeutic target.Recently, a humanized monoclonal antibody, calledBapineuzumab, was reported. This antibody binds with highaffinity to the neurotoxic free N-terminus Aβ peptides (Aβ ) but WTclinical trials in patients with moderate AD show thatBapineuzumab fails to improve the cognitive ability of patients[1].In addition to the Aβ peptides present in the human brain, WTthere are Aβ peptides N-terminal truncated in the residues Glu3(AβN3(pE)) and Glu11 (AβN11(pE)). Among these species,AβN3(pE) is a major N-truncated constituent of intracellular,extracellular and vascular Aβ deposits in AD brain tissue [2].A possible explanation of Bapineuzumab failure in cognitiveimprovement of AD patients is that the N-terminal modifiedpeptides are the main component of senile plaques, whichconstitute more than 50% of the Aβ in neuritic plaques . In turn,Bapineuzumab presents low affinity on these N-terminalmodified Aβ-peptides found in amyloid deposits with respectto the Aβ peptides. The sum of these factors might be the WTcause for the loss of the efficacy of Bapineuzumab for treatingof AD.Several factors might be responsibles of Bapineuzumabfailure as a therapeutic agent against AD, this hypothesis is veryinteresting and well-founded and therefore, it should be takeninto account. Furthermore, although it is well known thatBapinezumab has less affinity for the Aβ N-terminal modifiedwith respect to Aβ , the question which arises is what is the WTcause of this different affinity?The main objective of the present study is the investigationof the interactions between the Aβ peptide isoforms (Aβ and WTAβN3(pE)) and Bapineuzumab using computationalcalculations. This study would allow us to understand betterhow this antibody interacts with the amino acid residues of thedifferent Aβ peptides. This basic structural information can beuseful for a deeper understanding about the scope andlimitations of Bapineuzumab as a therapeutical agent for theAD.